C7 carbonate taxane compositions

ABSTRACT

Taxanes having a carbonate substituent at C(7), a hydroxy substituent at C(10), and a range of C(2), C(9), C(14), and side chain substituents.

REFERENCE TO RELATED APPLICATION

[0001] This application is a continuation based on Ser. No. 09/776,137filed Feb. 2, 2001 which claims priority from U.S. provisionalapplication Serial No. 60/179,671, filed on Feb. 2, 2000.

BACKGROUND OF THE INVENTION

[0002] The present invention is directed to novel taxanes which haveexceptional utility as antitumor agents.

[0003] The taxane family of terpenes, of which baccatin III and taxolare members, has been the subject of considerable interest in both thebiological and chemical arts. Taxol itself is employed as a cancerchemotherapeutic agent and possesses a broad range of tumor-inhibitingactivity. Taxol has a 2′R, 3′S configuration and the followingstructural formula:

[0004] wherein Ac is acetyl.

[0005] Colin et al. reported in U.S. Pat. No. 4,814,470 that certaintaxol analogs have an activity significantly greater than that of taxol.One of these analogs, commonly referred to as docetaxel, has thefollowing structural formula:

[0006] Although taxol and docetaxel are useful chemotherapeutic agents,there are limitations on their effectiveness, including limited efficacyagainst certain types of cancers and toxicity to subjects whenadministered at various doses. Accordingly, a need remains foradditional chemotherapeutic agents with improved efficacy and lesstoxicity.

SUMMARY OF THE INVENTION

[0007] Among the objects of the present invention, therefore, is theprovision of taxanes which compare favorably to taxol and docetaxel withrespect to efficacy as anti-tumor agents and with respect to toxicity.In general, these taxanes possess a carbonate substituent at C-7, ahydroxy substituent at C-10, and a range of C(2), C(9), C(14), and C(13)side chain substituents.

[0008] Briefly, therefore, the present invention is directed to thetaxane composition, per se, to pharmaceutical compositions comprisingthe taxane and a pharmaceutically acceptable carrier, and to methods ofadministration.

[0009] Other objects and features of this invention will be in partapparent and in part pointed out hereinafter.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] In one embodiment of the present invention, the taxanes of thepresent invention correspond to structure (1):

[0011] wherein

[0012] R₂ is acyloxy;

[0013] R₇ is carbonate;

[0014] R₉ is keto, hydroxy, or acyloxy;

[0015] R₁₀ is hydroxy;

[0016] R₁₄ is hydrido or hydroxy;

[0017] X₃ is substituted or unsubstituted alkyl, alkenyl, alkynyl,phenyl or heterocyclo, wherein alkyl comprises at least two carbonatoms;

[0018] X₅ is —COX₁₀, —COOX₁₀, or —CONHX₁₀;

[0019] X₁₀ is hydrocarbyl, substituted hydrocarbyl, or heterocyclo;

[0020] Ac is acetyl; and

[0021] R₇, R₉, and R₁₀ independently have the alpha or betastereochemical configuration.

[0022] In one embodiment, R₂ is an ester (R_(2a)C(O)O—), a carbamate(R_(2a)R_(2b)NC(O)O—), a carbonate (R_(2a)OC(O)O—), or a thiocarbamate(R_(2a)SC(O)O—) wherein R_(2a) and R_(2b) are independently hydrogen,hydrocarbyl, substituted hydrocarbyl or heterocyclo. In a preferredembodiment, R₂ is an ester (R_(2a)C(O)O—), wherein R_(2a) is aryl orheteroaromatic. In another preferred embodiment, R₂ is an ester(R_(2a)C(O)O—), wherein R_(2a) is substituted or unsubstituted phenyl,furyl, thienyl, or pyridyl. In one particularly preferred embodiment, R₂is benzoyloxy.

[0023] In one embodiment, R₇ is R_(7a)OCOO— wherein R_(7a) is (i)substituted or unsubstituted C₁ to C₈ alkyl (straight, branched orcyclic), such as methyl, ethyl, propyl, butyl, pentyl, or hexyl; (ii)substituted or unsubstituted C₂ to C₈ alkenyl (straight, branched orcyclic), such as ethenyl, propenyl, butenyl, pentenyl or hexenyl; (iii)substituted or unsubstituted C₂ to C₈ alkynyl (straight or branched)such as ethynyl, propynyl, butynyl, pentynyl, or hexynyl; (iv)substituted or unsubstituted phenyl; or (v) substituted or unsubstitutedheterocyclo such as furyl, thienyl, or pyridyl. The substituents may behydrocarbyl or any of the heteroatom containing substituents identifiedelsewhere herein for substituted hydrocarbyl. In a preferred embodiment,R_(7a) is methyl, ethyl, straight, branched or cyclic propyl, straight,branched or cyclic butyl, straight, branched or cyclic hexyl, straightor branched propenyl, isobutenyl, furyl or thienyl. In anotherembodiment, R_(7a) is substituted ethyl, substituted propyl (straight,branched or cyclic), substituted propenyl (straight or branched),substituted isobutenyl, substituted furyl or substituted thienyl whereinthe substituent(s) is/are selected from the group consisting ofheterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protectedhydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal, acetal, esterand ether moieties, but not phosphorous containing moieties.

[0024] While R₉ is keto in one embodiment of the present invention, inother embodiments R₉ may have the alpha or beta stereochemicalconfiguration, preferably the beta stereochemical configuration, and maybe, for example, α- or β-hydroxy or α- or β-acyloxy. For example, whenR₉ is acyloxy, it may be an ester (R_(9a)C(O)O—), a carbamate(R_(9a)R_(9b)NC(O)O—), a carbonate (R_(9a)OC(O)O—), or a thiocarbamate(R_(9a)SC(O)O—) wherein R_(9a) and R_(9b) are independently hydrogen,hydrocarbyl, substituted hydrocarbyl or heterocyclo. If R₉ is an ester(R_(9a)C(O)O—), R_(9a) is substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstituted arylor substituted or unsubstituted heteroaromatic. Still more preferably,R₉ is an ester (R_(9a)C(O)O—), wherein R_(9a) is substituted orunsubstituted phenyl, substituted or unsubstituted furyl, substituted orunsubstituted thienyl, or substituted or unsubstituted pyridyl. In oneembodiment R₉ is (R_(9a)C(O)O—) wherein R_(9a) is methyl, ethyl, propyl(straight, branched or cyclic), butyl (straight, branched or cyclic),pentyl, (straight, branched or cyclic), or hexyl (straight, branched orcyclic). In another embodiment R₉ is (R_(9a)C(O)O—) wherein R_(9a) issubstituted methyl, substituted ethyl, substituted propyl (straight,branched or cyclic), substituted butyl (straight, branched or cyclic),substituted pentyl, (straight, branched or cyclic), or substituted hexyl(straight, branched or cyclic) wherein the substituent(s) is/areselected from the group consisting of heterocyclo, alkoxy, alkenoxy,alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro,amino, amido, thiol, ketal, acetal, ester and ether moieties, but notphosphorous containing moieties.

[0025] Exemplary X₃ substituents include substituted or unsubstituted C₂to C₈ alkyl, substituted or unsubstituted C₂ to C₈ alkenyl, substitutedor unsubstituted C₂ to C₈ alkynyl, substituted or unsubstitutedheteroaromatics containing 5 or 6 ring atoms, and substituted orunsubstituted phenyl. Exemplary preferred X₃ substituents includesubstituted or unsubstituted ethyl, propyl, butyl, cyclopropyl,cyclobutyl, cyclohexyl, isobutenyl, furyl, thienyl, and pyridyl.

[0026] Exemplary X₅ substituents include —COX₁₀, —COOX₁₀ or —CONHX₁₀wherein X₁₀ is substituted or unsubstituted alkyl, alkenyl, phenyl orheteroaromatic. Exemplary preferred X₅ substituents include —COX₁₀,—COOX₁₀ or —CONHX₁₀ wherein X₁₀ is (i) substituted or unsubstituted C₁to C₈ alkyl such as substituted or unsubstituted methyl, ethyl, propyl(straight, branched or cyclic), butyl (straight, branched or cyclic),pentyl (straight, branched or cyclic), or hexyl (straight, branched orcyclic); (ii) substituted or unsubstituted C₂ to C₈ alkenyl such assubstituted or unsubstituted ethenyl, propenyl (straight, branched orcyclic), butenyl (straight, branched or cyclic), pentenyl (straight,branched or cyclic) or hexenyl (straight, branched or cyclic); (iii)substituted or unsubstituted C₂ to C₈ alkynyl such as substituted orunsubstituted ethynyl, propynyl (straight or branched), butynyl(straight or branched), pentynyl (straight or branched), or hexynyl(straight or branched); (iv) substituted or unsubstituted phenyl, or (v)substituted or unsubstituted heteroaromatic such as furyl, thienyl, orpyridyl, wherein the substituent(s) is/are selected from the groupconsisting of heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy,protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal,acetal, ester and ether moieties, but not phosphorous containingmoieties.

[0027] In one embodiment, the taxanes of the present inventioncorrespond to structure (2):

[0028] wherein

[0029] R₇ is carbonate;

[0030] R₁₀ is hydroxy;

[0031] X₃ is substituted or unsubstituted alkyl, alkenyl, alkynyl, orheterocyclo, wherein alkyl comprises at least two carbon atoms;

[0032] X₅ is —COX₁₀, —COOX₁₀, or —CONHX₁₀; and

[0033] X₁₀ is hydrocarbyl, substituted hydrocarbyl, or heterocyclo.

[0034] For example, in this preferred embodiment in which the taxanecorresponds to structure (2), R₇ may be R_(7a)OCOO— wherein R_(7a) issubstituted or unsubstituted methyl, ethyl, propyl, butyl, pentyl orhexyl, more preferably substituted or unsubstituted methyl, ethyl orpropyl, still more preferably substituted or unsubstituted methyl,ethyl, and still more preferably unsubstituted methyl or ethyl. WhileR_(7a) is selected from among these, in one embodiment X₃ is selectedfrom substituted or unsubstituted alkyl, alkenyl, phenyl or heterocyclo,more preferably substituted or unsubstituted alkenyl, phenyl orheterocyclo, still more preferably substituted or unsubstituted phenylor heterocyclo, and still more preferably heterocyclo such as furyl,thienyl or pyridyl. While R_(7a) and X₃ are selected from among these,in one embodiment X₅ is selected from —COX₁₀ wherein X₁₀ is phenyl,alkyl or heterocyclo, more preferably phenyl. Alternatively, whileR_(7a) and X₃ are selected from among these, in one embodiment X₅ isselected from —COX₁₀ wherein X₁₀ is phenyl, alkyl or heterocyclo, morepreferably phenyl, or X₅ is —COOX₁₀ wherein X₁₀ is alkyl, preferablyt-butyl. Among the more preferred embodiments, therefore, are taxanescorresponding to structure 2 in which (i) X₅ is —COOX₁₀ wherein X₁₀ istert-butyl or X₅ is —COX₁₀ wherein X₁₀ is phenyl, (ii) X₃ is substitutedor unsubstituted cycloalkyl, alkenyl, phenyl or heterocyclo, morepreferably substituted or unsubstituted isobutenyl, phenyl, furyl,thienyl, or pyridyl, still more preferably unsubstituted isobutenyl,furyl, thienyl or pyridyl, and (iii) R_(7a) is unsubstituted methyl,ethyl or propyl, more preferably methyl or ethyl.

[0035] Among the preferred embodiments, therefore, are taxanescorresponding to structure 1 or 2 wherein R₇ is R_(7a)OCOO— whereinR_(7a) is methyl. In this embodiment, X₃ is preferably cycloalkyl,isobutenyl, phenyl, substituted phenyl such as p-nitrophenyl, orheterocyclo, more preferably heterocyclo, still more preferably furyl,thienyl or pyridyl; and X₅ is preferably benzoyl, alkoxycarbonyl, orheterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl. In one alternative of this embodiment, X₃ isheterocyclo; X₅ is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, morepreferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still morepreferably t-butoxycarbonyl; R₂ is benzoyl, R₉ is keto and R₁₄ ishydrido. In another alternative of this embodiment, X₃ is heterocyclo;X₅ is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferablybenzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferablyt-butoxycarbonyl; R₂ is benzoyl, R₉ is keto and R₁₄ is hydrido. Inanother alternative of this embodiment, X₃ is heterocyclo; X₅ isbenzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferablybenzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferablyt-butoxycarbonyl; R₂ is benzoyl, R₉ is keto and R₁₄ is hydroxy. Inanother alternative of this embodiment, X₃ is heterocyclo; X₅ isbenzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferablybenzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferablyt-butoxycarbonyl; R₂ is benzoyl, R₉ is hydroxy and R₁₄ is hydroxy. Inanother alternative of this embodiment, X₃ is heterocyclo; X₅ isbenzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferablybenzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferablyt-butoxycarbonyl; R₂ is benzoyl, R₉ is hydroxy and R₁₄ is hydrido. Inanother alternative of this embodiment, X₃ is heterocyclo; X₅ isbenzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferablybenzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferablyt-butoxycarbonyl; R₂ is benzoyl, R₉ is acyloxy and R₁₄ is hydroxy. Inanother alternative of this embodiment, X₃ is heterocyclo; X₅ isbenzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferablybenzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferablyt-butoxycarbonyl; R₂ is benzoyl, R₉ is acyloxy and R₁₄ is hydrido. Ineach of the alternatives of this embodiment when the taxane hasstructure 1, R₇ and R₁₀ may each have the beta stereochemicalconfiguration, R₇ and R₁₀ may each have the alpha stereochemicalconfiguration, R₇ may have the alpha stereochemical configuration whileR₁₀ has the beta stereochemical configuration or R₇ may have the betastereochemical configuration while R₁₀ has the alpha stereochemicalconfiguration.

[0036] Also among the preferred embodiments are taxanes corresponding tostructure 1 or 2 wherein R₇ is R_(7a)OCOO— wherein R_(7a) is ethyl. Inthis embodiment, X₃ is preferably cycloalkyl, isobutenyl, phenyl,substituted phenyl such as p-nitrophenyl, or heterocyclo, morepreferably heterocyclo, still more preferably furyl, thienyl or pyridyl;and X₅ is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl,more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl. In onealternative of this embodiment, X₃ is heterocyclo; X₅ is benzoyl,alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl,t-butoxycarbonyl or t-amyloxycarbonyl, still more preferablyt-butoxycarbonyl; R₂ is benzoyl, R₉ is keto and R₁₄ is hydrido. Inanother alternative of this embodiment, X₃ is heterocyclo; X₅ isbenzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferablybenzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferablyt-butoxycarbonyl; R₂ is benzoyl, R₉ is keto and R₁₄ is hydrido. Inanother alternative of this embodiment, X₃ is heterocyclo; X₅ isbenzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferablybenzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferablyt-butoxycarbonyl; R₂ is benzoyl, R₉ is keto and R₁₄ is hydroxy. Inanother alternative of this embodiment, X₃ is heterocyclo; X₅ isbenzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferablybenzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferablyt-butoxycarbonyl; R₂ is benzoyl, R₉ is hydroxy and R₁₄ is hydroxy. Inanother alternative of this embodiment, X₃ is heterocyclo; X₅ isbenzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferablybenzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferablyt-butoxycarbonyl; R₂ is benzoyl, R₉ is hydroxy and R₁₄ is hydrido. Inanother alternative of this embodiment, X₃ is heterocyclo; X₅ isbenzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferablybenzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferablyt-butoxycarbonyl; R₂ is benzoyl, R₉ is acyloxy and R₁₄ is hydroxy. Inanother alternative of this embodiment, X₃ is heterocyclo; X₅ isbenzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferablybenzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferablyt-butoxycarbonyl; R₂ is benzoyl, R₉ is acyloxy and R₁₄ is hydrido. Ineach of the alternatives of this embodiment when the taxane hasstructure 1, R₇ and R₁₀ may each have the beta stereochemicalconfiguration, R₇ and R₁₀ may each have the alpha stereochemicalconfiguration, R₇ may have the alpha stereochemical configuration whileR₁₀ has the beta stereochemical configuration or R₇ may have the betastereochemical configuration while R₁₀ has the alpha stereochemicalconfiguration.

[0037] Also among the preferred embodiments are taxanes corresponding tostructure 1 or 2 wherein R₇ is R_(7a)OCOO— wherein R_(7a) is propyl. Inthis embodiment, X₃ is preferably cycloalkyl, isobutenyl, phenyl,substituted phenyl such as p-nitrophenyl, or heterocyclo, morepreferably heterocyclo, still more preferably furyl, thienyl or pyridyl;and X₅ is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl,more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl. In onealternative of this embodiment, X₃ is heterocyclo; X₅ is benzoyl,alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl,t-butoxycarbonyl or t-amyloxycarbonyl, still more preferablyt-butoxycarbonyl; R₂ is benzoyl, R₉ is keto and R₁₄ is hydrido. Inanother alternative of this embodiment, X₃ is heterocyclo; X₅ isbenzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferablybenzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferablyt-butoxycarbonyl; R₂ is benzoyl, R₉ is keto and R₁₄ is hydrido. Inanother alternative of this embodiment, X₃ is heterocyclo; X₅ isbenzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferablybenzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferablyt-butoxycarbonyl; R₂ is benzoyl, R₉ is keto and R₁₄ is hydroxy. Inanother alternative of this embodiment, X₃ is heterocyclo; X₅ isbenzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferablybenzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferablyt-butoxycarbonyl; R₂ is benzoyl, R₉ is hydroxy and R₁₄ is hydroxy. Inanother alternative of this embodiment, X₃ is heterocyclo; X₅ isbenzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferablybenzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferablyt-butoxycarbonyl; R₂ is benzoyl, R₉ is hydroxy and R₁₄ is hydrido. Inanother alternative of this embodiment, X₃ is heterocyclo; X₅ isbenzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferablybenzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferablyt-butoxycarbonyl; R₂ is benzoyl, R₉ is acyloxy and R₁₄ is hydroxy. Inanother alternative of this embodiment, X₃ is heterocyclo; X₅ isbenzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferablybenzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferablyt-butoxycarbonyl; R₂ is benzoyl, R₉ is acyloxy and R₁₄ is hydrido. Ineach of the alternatives of this embodiment when the taxane hasstructure 1, R₇ and R₁₀ may each have the beta stereochemicalconfiguration, R₇ and R₁₀ may each have the alpha stereochemicalconfiguration, R₇ may have the alpha stereochemical configuration whileR₁₀ has the beta stereochemical configuration or R₇ may have the betastereochemical configuration while R₁₀ has the alpha stereochemicalconfiguration.

[0038] Taxanes having the general formula 1 may be obtained by treatmentof a β-lactam with an alkoxide having the taxane tetracyclic nucleus anda C-13 metallic oxide substituent to form compounds having a β-amidoester substituent at C-13 (as described more fully in Holton U.S. Pat.No. 5,466,834), followed by removal of the hydroxy protecting groups.The β-lactam has the following structural formula (3):

[0039] wherein P₂ is a hydroxy protecting group and X₃ and X₅ are aspreviously defined and the alkoxide has the structural formula (4):

[0040] wherein M is a metal or ammonium, P₁₀ is a hydroxy protectinggroup and R₂, R₉, R₇ and R₁₄ are as previously defined.

[0041] Alkoxide 4 may be prepared from 10-deacetylbaccatin III (or aderivative thereof) by selective protection of the C-10 hydroxyl groupand then acylation of the C-7 hydroxyl group followed by treatment witha metallic amide. In one embodiment of the present invention, the C(10)hydroxyl group of 10-deacetylbaccatin III is selectively protected witha silyl group using, for example, a silylamide or bissilyamide as asilylating agent. Preferred silylating agents includetri(hydrocarbyl)silyl-trifluoromethylacetamides and bistri(hydrocarbyl)-silyltrifluoromethylacetamides (with the hydrocarbylmoiety being substituted or unsubstituted alkyl or aryl) such asN,O-bis-(trimethylsilyl) trifluoroacetamide,N,O-bis-(triethylsilyl)trifluoroacetamide,N-methyl-N-triethylsilyltrifluoroacetamide, andN,O-bis(t-butyldimethylsilyl)trifluoroacetamide. The silylating agentsmay be used either alone or in combination with a catalytic amount of abase such as an alkali metal base. Alkali metal amides, such as lithiumamide catalysts, in general, and lithium hexamethyldisilazide, inparticular, are preferred. The solvent for the selective silylationreaction is preferably an ethereal solvent such as tetrahydrofuran.Alternatively, however, other solvents such as ether or dimethoxyethanemay be used. The temperature at which the C(10) selective silylation iscarried out is not narrowly critical. In general, however, it is carriedout at 0° C. or greater.

[0042] Selective acylation of the C(7) hydroxyl group of a C(10)protected taxane to form a C(7) carbonate can be achieved using any of avariety of common acylating agents such as a haloformates. In general,acylation of the C(7) hydroxy group of a C(10) protected taxane are moreefficient and more selective than are C(7) acylations of a7,10-dihydroxy taxane such as 10-DAB; stated another way, once the C(10)hydroxyl group has been protected, there is a significant difference inthe reactivity of the remaining C(7), C(13), and C(1) hydroxyl groups.These acylation reactions may optionally be carried out in the presenceor absence of an amine base.

[0043] Derivatives of 10-deacetylbaccatin III having alternativesubstituents at C(2), C(9) and C(14) and processes for their preparationare known in the art. Taxane derivatives having acyloxy substituentsother than benzoyloxy at C(2) may be prepared, for example, as describedin Holton et al., U.S. Pat. No. 5,728,725 or Kingston et al., U.S. Pat.No. 6,002,023. Taxanes having acyloxy or hydroxy substituents at C(9) inplace of keto may be prepared, for example as described in Holton etal., U.S. Pat. No. 6,011,056 or Gunawardana et al., U.S. Pat. No.5,352,806. Taxanes having a beta hydroxy substituent at C(14) may beprepared from naturally occurring 14-hydroxy-10-deacetylbaccatin III.

[0044] Processes for the preparation and resolution of the β-lactamstarting material are generally well known. For example, the β-lactammay be prepared as described in Holton, U.S. Pat. No. 5,430,160 and theresulting enatiomeric mixtures of β-lactams may be resolved by astereoselective hydrolysis using a lipase or enzyme as described, forexample, in Patel, U.S. Pat. No. 5,879,929 Patel U.S. Pat. No. 5,567,614or a liver homogenate as described, for example, in PCT PatentApplication No. 00/41204. In a preferred embodiment in which theβ-lactam is furyl substituted at the C(4) position, the β-lactam can beprepared as illustrated in the following reaction scheme:

[0045] wherein Ac is acetyl, NEt₃ is triethylamine, CAN is cericammonium nitrate, and p-TsOH is p-toluenesulfonic acid. The beef liverresolution may be carried out, for example, by combining the enatiomericβ-lactam mixture with a beef liver suspension (prepared, for example, byadding 20 g of frozen beef liver to a blender and then adding a pH 8buffer to make a total volume of 1 L).

[0046] Compounds of formula 1 of the instant invention are useful forinhibiting tumor growth in mammals including humans and are preferablyadministered in the form of a pharmaceutical composition comprising aneffective antitumor amount of a compound of the instant invention incombination with at least one pharmaceutically or pharmacologicallyacceptable carrier. The carrier, also known in the art as an excipient,vehicle, auxiliary, adjuvant, or diluent, is any substance which ispharmaceutically inert, confers a suitable consistency or form to thecomposition, and does not diminish the therapeutic efficacy of theantitumor compounds. The carrier is “pharmaceutically orpharmacologically acceptable” if it does not produce an adverse,allergic or other untoward reaction when administered to a mammal orhuman, as appropriate.

[0047] The pharmaceutical compositions containing the antitumorcompounds of the present invention may be formulated in any conventionalmanner. Proper formulation is dependent upon the route of administrationchosen. The compositions of the invention can be formulated for anyroute of administration so long as the target tissue is available viathat route. Suitable routes of administration include, but are notlimited to, oral, parenteral (e.g., intravenous, intraarterial,subcutaneous, rectal, subcutaneous, intramuscular, intraorbital,intracapsular, intraspinal, intraperitoneal, or intrasternal), topical(nasal, transdermal, intraocular), intravesical, intrathecal, enteral,pulmonary, intralymphatic, intracavital, vaginal, transurethral,intradermal, aural, intramammary, buccal, orthotopic, intratracheal,intralesional, percutaneous, endoscopical, transmucosal, sublingual andintestinal administration.

[0048] Pharmaceutically acceptable carriers for use in the compositionsof the present invention are well known to those of ordinary skill inthe art and are selected based upon a number of factors: the particularantitumor compound used, and its concentration, stability and intendedbioavailability; the disease, disorder or condition being treated withthe composition; the subject, its age, size and general condition; andthe route of administration. Suitable carriers are readily determined byone of ordinary skill in the art (see, for example, J. G. Nairn, in:Remington's Pharmaceutical Science (A. Gennaro, ed.), Mack PublishingCo., Easton, Pa., (1985), pp. 1492-1517, the contents of which areincorporated herein by reference).

[0049] The compositions are preferably formulated as tablets,dispersible powders, pills, capsules, gelcaps, caplets, gels, liposomes,granules, solutions, suspensions, emulsions, syrups, elixirs, troches,dragees, lozenges, or any other dosage form which can be administeredorally. Techniques and compositions for making oral dosage forms usefulin the present invention are described in the following references: 7Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors,1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981);and Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition(1976).

[0050] The compositions of the invention for oral administrationcomprise an effective antitumor amount of a compound of the invention ina pharmaceutically acceptable carrier. Suitable carriers for soliddosage forms include sugars, starches, and other conventional substancesincluding lactose, talc, sucrose, gelatin, carboxymethylcellulose, agar,mannitol, sorbitol, calcium phosphate, calcium carbonate, sodiumcarbonate, kaolin, alginic acid, acacia, corn starch, potato starch,sodium saccharin, magnesium carbonate, tragacanth, microcrystallinecellulose, colloidal silicon dioxide, croscarmellose sodium, talc,magnesium stearate, and stearic acid. Further, such solid dosage formsmay be uncoated or may be coated by known techniques; e.g., to delaydisintegration and absorption.

[0051] The antitumor compounds of the present invention are alsopreferably formulated for parenteral administration, e.g., formulatedfor injection via intravenous, intraarterial, subcutaneous, rectal,subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal,intraperitoneal, or intrasternal routes. The compositions of theinvention for parenteral administration comprise an effective antitumoramount of the antitumor compound in a pharmaceutically acceptablecarrier. Dosage forms suitable for parenteral administration includesolutions, suspensions, dispersions, emulsions or any other dosage formwhich can be administered parenterally. Techniques and compositions formaking parenteral dosage forms are known in the art.

[0052] Suitable carriers used in formulating liquid dosage forms fororal or parenteral administration include nonaqueous,pharmaceutically-acceptable polar solvents such as oils, alcohols,amides, esters, ethers, ketones, hydrocarbons and mixtures thereof, aswell as water, saline solutions, dextrose solutions (e.g., DW5),electrolyte solutions, or any other aqueous, pharmaceutically acceptableliquid.

[0053] Suitable nonaqueous, pharmaceutically-acceptable polar solventsinclude, but are not limited to, alcohols (e.g., α-glycerol formal,β-glycerol formal, 1,3-butyleneglycol, aliphatic or aromatic alcoholshaving 2-30 carbon atoms such as methanol, ethanol, propanol,isopropanol, butanol, t-butanol, hexanol, octanol, amylene hydrate,benzyl alcohol, glycerin (glycerol), glycol, hexylene glycol,tetrahydrofurfuryl alcohol, lauryl alcohol, cetyl alcohol, or stearylalcohol, fatty acid esters of fatty alcohols such as polyalkyleneglycols (e.g., polypropylene glycol, polyethylene glycol), sorbitan,sucrose and cholesterol); amides (e.g., dimethylacetamide (DMA), benzylbenzoate DMA, dimethylformamide, N-(β-hydroxyethyl)-lactamide, N,N-dimethylacetamide-amides, 2-pyrrolidinone, 1-methyl-2-pyrrolidinone,or polyvinylpyrrolidone); esters (e.g., 1-methyl-2-pyrrolidinone,2-pyrrolidinone, acetate esters such as monoacetin, diacetin, andtriacetin, aliphatic or aromatic esters such as ethyl caprylate oroctanoate, alkyl oleate, benzyl benzoate, benzyl acetate,dimethylsulfoxide (DMSO), esters of glycerin such as mono, di, ortri-glyceryl citrates or tartrates, ethyl benzoate, ethyl acetate, ethylcarbonate, ethyl lactate, ethyl oleate, fatty acid esters of sorbitan,fatty acid derived PEG esters, glyceryl monostearate, glyceride esterssuch as mono, di, or tri-glycerides, fatty acid esters such as isopropylmyristrate, fatty acid derived PEG esters such as PEG-hydroxyoleate andPEG-hydroxystearate, N-methyl pyrrolidinone, pluronic 60,polyoxyethylene sorbitol oleic polyesters such as poly(ethoxylated)₃₀₋₆₀sorbitol poly(oleate)₂₋₄, poly(oxyethylene)₁₅₋₂₀ monooleate,poly(oxyethylene)₁₅₋₂₀ mono 12-hydroxystearate, andpoly(oxyethylene)₁₅₋₂₀ mono ricinoleate, polyoxyethylene sorbitan esterssuch as polyoxyethylene-sorbitan monooleate, polyoxyethylene-sorbitanmonopalmitate, polyoxyethylene-sorbitan monolaurate,polyoxyethylene-sorbitan monostearate, and Polysorbate® 20, 40, 60 or 80from ICI Americas, Wilmington, Del., polyvinylpyrrolidone, alkyleneoxymodified fatty acid esters such as polyoxyl 40 hydrogenated castor oiland polyoxyethylated castor oils (e.g., Cremophor® EL solution orCremophor® RH 40 solution), saccharide fatty acid esters (i.e., thecondensation product of a monosaccharide (e.g., pentoses such as ribose,ribulose, arabinose, xylose, lyxose and xylulose, hexoses such asglucose, fructose, galactose, mannose and sorbose, trioses, tetroses,heptoses, and octoses), disaccharide (e.g., sucrose, maltose, lactoseand trehalose) or oligosaccharide or mixture thereof with a C₄-C₂₂ fattyacid(s)(e.g., saturated fatty acids such as caprylic acid, capric acid,lauric acid, myristic acid, palmitic acid and stearic acid, andunsaturated fatty acids such as palmitoleic acid, oleic acid, elaidicacid, erucic acid and linoleic acid)), or steroidal esters); alkyl,aryl, or cyclic ethers having 2-30 carbon atoms (e.g., diethyl ether,tetrahydrofuran, dimethyl isosorbide, diethylene glycol monoethylether); glycofurol (tetrahydrofurfuryl alcohol polyethylene glycolether); ketones having 3-30 carbon atoms (e.g., acetone, methyl ethylketone, methyl isobutyl ketone); aliphatic, cycloaliphatic or aromatichydrocarbons having 4-30 carbon atoms (e.g., benzene, cyclohexane,dichloromethane, dioxolanes, hexane, n-decane, n-dodecane, n-hexane,sulfolane, tetramethylenesulfon, tetramethylenesulfoxide, toluene,dimethylsulfoxide (DMSO), or tetramethylenesulfoxide); oils of mineral,vegetable, animal, essential or synthetic origin (e.g., mineral oilssuch as aliphatic or wax-based hydrocarbons, aromatic hydrocarbons,mixed aliphatic and aromatic based hydrocarbons, and refined paraffinoil, vegetable oils such as linseed, tung, safflower, soybean, castor,cottonseed, groundnut, rapeseed, coconut, palm, olive, corn, corn germ,sesame, persic and peanut oil and glycerides such as mono-, di- ortriglycerides, animal oils such as fish, marine, sperm, cod-liver,haliver, squalene, squalane, and shark liver oil, oleic oils, andpolyoxyethylated castor oil); alkyl or aryl halides having 1-30 carbonatoms and optionally more than one halogen substituent; methylenechloride; monoethanolamine; petroleum benzin; trolamine; omega-3polyunsaturated fatty acids (e.g., alpha-linolenic acid,eicosapentaenoic acid, docosapentaenoic acid, or docosahexaenoic acid);polyglycol ester of 12-hydroxystearic acid and polyethylene glycol(Solutol® HS-15, from BASF, Ludwigshafen, Germany); polyoxyethyleneglycerol; sodium laurate; sodium oleate; or sorbitan monooleate.

[0054] Other pharmaceutically acceptable solvents for use in theinvention are well known to those of ordinary skill in the art, and areidentified in The Chemotherapy Source Book (Williams & WilkensPublishing), The Handbook of Pharmaceutical Excipients, (AmericanPharmaceutical Association, Washington, D.C., and The PharmaceuticalSociety of Great Britain, London, England, 1968), Modern Pharmaceutics,(G. Banker et al., eds., 3d ed.)(Marcel Dekker, Inc., New York, N.Y.,1995), The Pharmacological Basis of Therapeutics, (Goodman & Gilman,McGraw Hill Publishing), Pharmaceutical Dosage Forms, (H. Lieberman etal., eds., )(Marcel Dekker, Inc., New York, N.Y., 1980), Remington'sPharmaceutical Sciences (A. Gennaro, ed., 19th ed.)(Mack Publishing,Easton, Pa., 1995), The United States Pharmacopeia 24, The NationalFormulary 19, (National Publishing, Philadelphia, Pa., 2000), A. J.Spiegel et al., and Use of Nonaqueous Solvents in Parenteral Products,JOURNAL OF PHARMACEUTICAL SCIENCES, Vol. 52, No. 10, pp. 917-927 (1963).

[0055] Preferred solvents include those known to stabilize the antitumorcompounds, such as oils rich in triglycerides, for example, saffloweroil, soybean oil or mixtures thereof, and alkyleneoxy modified fattyacid esters such as polyoxyl 40 hydrogenated castor oil andpolyoxyethylated castor oils (e.g., Cremophor® EL solution or Cremophor®RH 40 solution). Commercially available triglycerides includeIntralipid® emulsified soybean oil (Kabi-Pharmacia Inc., Stockholm,Sweden), Nutralipid® emulsion (McGaw, Irvine, Calif.), Liposyn® II 20%emulsion (a 20% fat emulsion solution containing 100 mg safflower oil,100 mg soybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml ofsolution; Abbott Laboratories, Chicago, Ill.), Liposyn® III 2% emulsion(a 2% fat emulsion solution containing 100 mg safflower oil, 100 mgsoybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml ofsolution; Abbott Laboratories, Chicago, Ill.), natural or syntheticglycerol derivatives containing the docosahexaenoyl group at levelsbetween 25% and 100% by weight based on the total fatty acid content(Dhasco® (from Martek Biosciences Corp., Columbia, Md.), DHA Maguro®(from Daito Enterprises, Los Angeles, Calif.), Soyacal®, andTravemulsion®. Ethanol is a preferred solvent for use in dissolving theantitumor compound to form solutions, emulsions, and the like.

[0056] Additional minor components can be included in the compositionsof the invention for a variety of purposes well known in thepharmaceutical industry. These components will for the most part impartproperties which enhance retention of the antitumor compound at the siteof administration, protect the stability of the composition, control thepH, facilitate processing of the antitumor compound into pharmaceuticalformulations, and the like. Preferably, each of these components isindividually present in less than about 15 weight % of the totalcomposition, more preferably less than about 5 weight %, and mostpreferably less than about 0.5 weight % of the total composition. Somecomponents, such as fillers or diluents, can constitute up to 90 wt.% ofthe total composition, as is well known in the formulation art. Suchadditives include cryoprotective agents for preventing reprecipitationof the taxane, surface active, wetting or emulsifying agents (e.g.,lecithin, polysorbate-80, Tween® 80, pluronic 60, polyoxyethylenestearate ), preservatives (e.g., ethyl-p-hydroxybenzoate), microbialpreservatives (e.g., benzyl alcohol, phenol, m-cresol, chlorobutanol,sorbic acid, thimerosal and paraben), agents for adjusting pH orbuffering agents (e.g., acids, bases, sodium acetate, sorbitanmonolaurate), agents for adjusting osmolarity (e.g., glycerin),thickeners (e.g., aluminum monostearate, stearic acid, cetyl alcohol,stearyl alcohol, guar gum, methyl cellulose, hydroxypropylcellulose,tristearin, cetyl wax esters, polyethylene glycol), colorants, dyes,flow aids, non-volatile silicones (e.g., cyclomethicone), clays (e.g.,bentonites), adhesives, bulking agents, flavorings, sweeteners,adsorbents, fillers (e.g., sugars such as lactose, sucrose, mannitol, orsorbitol, cellulose, or calcium phosphate), diluents (e.g., water,saline, electrolyte solutions), binders (e.g., starches such as maizestarch, wheat starch, rice starch, or potato starch, gelatin, gumtragacanth, methyl cellulose, hydroxypropyl methylcellulose, sodiumcarboxymethyl cellulose, polyvinylpyrrolidone, sugars, polymers,acacia), disintegrating agents (e.g., starches such as maize starch,wheat starch, rice starch, potato starch, or carboxymethyl starch,cross-linked polyvinyl pyrrolidone, agar, alginic acid or a salt thereofsuch as sodium alginate, croscarmellose sodium or crospovidone),lubricants (e.g., silica, talc, stearic acid or salts thereof such asmagnesium stearate, or polyethylene glycol), coating agents (e.g.,concentrated sugar solutions including gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, or titanium dioxide),and antioxidants (e.g., sodium metabisulfite, sodium bisulfite, sodiumsulfite, dextrose, phenols, and thiophenols).

[0057] In a preferred embodiment, a pharmaceutical composition of theinvention comprises at least one nonaqueous, pharmaceutically acceptablesolvent and an antitumor compound having a solubility in ethanol of atleast about 100, 200, 300, 400, 500, 600, 700 or 800 mg/ml. While notbeing bound to a particular theory, it is believed that the ethanolsolubility of the antitumor compound may be directly related to itsefficacy. The antitumor compound can also be capable of beingcrystallized from a solution. In other words, a crystalline antitumorcompound, such as compound 1393, can be dissolved in a solvent to form asolution and then recrystallized upon evaporation of the solvent withoutthe formation of any amorphous antitumor compound. It is also preferredthat the antitumor compound have an ID50 value (i.e, the drugconcentration producing 50% inhibition of colony formation) of at least4, 5, 6, 7, 8, 9, or 10 times less that of paclitaxel when measuredaccording to the protocol set forth in the working examples.

[0058] Dosage form administration by these routes may be continuous orintermittent, depending, for example, upon the patient's physiologicalcondition, whether the purpose of the administration is therapeutic orprophylactic, and other factors known to and assessable by a skilledpractitioner.

[0059] Dosage and regimens for the administration of the pharmaceuticalcompositions of the invention can be readily determined by those withordinary skill in treating cancer. It is understood that the dosage ofthe antitumor compounds will be dependent upon the age, sex, health, andweight of the recipient, kind of concurrent treatment, if any, frequencyof treatment, and the nature of the effect desired. For any mode ofadministration, the actual amount of antitumor compound delivered, aswell as the dosing schedule necessary to achieve the advantageouseffects described herein, will also depend, in part, on such factors asthe bioavailability of the antitumor compound, the disorder beingtreated, the desired therapeutic dose, and other factors that will beapparent to those of skill in the art. The dose administered to ananimal, particularly a human, in the context of the present inventionshould be sufficient to effect the desired therapeutic response in theanimal over a reasonable period of time. Preferably, an effective amountof the antitumor compound, whether administered orally or by anotherroute, is any amount which would result in a desired therapeuticresponse when administered by that route. Preferably, the compositionsfor oral administration are prepared in such a way that a single dose inone or more oral preparations contains at least 20 mg of the antitumorcompound per m² of patient body surface area, or at least 50, 100, 150,200, 300, 400, or 500 mg of the antitumor compound per m² of patientbody surface area, wherein the average body surface area for a human is1.8 m². Preferably, a single dose of a composition for oraladministration contains from about 20 to about 600 mg of the antitumorcompound per m² of patient body surface area, more preferably from about25 to about 400 mg/m² even more preferably, from about 40 to about 300mg/m², and even more preferably from about 50 to about 200 mg/m².Preferably, the compositions for parenteral administration are preparedin such a way that a single dose contains at least 20 mg of theantitumor compound per m² of patient body surface area, or at least 40,50, 100,150, 200, 300, 400, or 500 mg of the antitumor compound per m²of patient body surface area. Preferably, a single dose in one or moreparenteral preparations contains from about 20 to about 500 mg of theantitumor compound per m² of patient body surface area, more preferablyfrom about 40 to about 400 mg/m^(2,) and even more preferably, fromabout 60 to about 350 mg/m². However, the dosage may vary depending onthe dosing schedule which can be adjusted as necessary to achieve thedesired therapeutic effect. It should be noted that the ranges ofeffective doses provided herein are not intended to limit the inventionand represent preferred dose ranges. The most preferred dosage will betailored to the individual subject, as is understood and determinable byone of ordinary skill in the art without undue experimentation.

[0060] The concentration of the antitumor compound in a liquidpharmaceutical composition is preferably between about 0.01 mg and about10 mg per ml of the composition, more preferably between about 0.1 mgand about 7 mg per ml, even more preferably between about 0.5 mg andabout 5 mg per ml, and most preferably between about 1.5 mg and about 4mg per ml. Relatively low concentrations are generally preferred becausethe antitumor compound is most soluble in the solution at lowconcentrations. The concentration of the antitumor compound in a solidpharmaceutical composition for oral administration is preferably betweenabout 5 weight % and about 50 weight %, based on the total weight of thecomposition, more preferably between about 8 weight % and about 40weight %, and most preferably between about 10 weight % and about 30weight %.

[0061] In one embodiment, solutions for oral administration are preparedby dissolving an antitumor compound in any pharmaceutically acceptablesolvent capable of dissolving the compound (e.g., ethanol or methylenechloride) to form a solution. An appropriate volume of a carrier whichis a solution, such as Cremophor® EL solution, is added to the solutionwhile stirring to form a pharmaceutically acceptable solution for oraladministration to a patient. If desired, such solutions can beformulated to contain a minimal amount of, or to be free of, ethanol,which is known in the art to cause adverse physiological effects whenadministered at certain concentrations in oral formulations.

[0062] In another embodiment, powders or tablets for oral administrationare prepared by dissolving an antitumor compound in any pharmaceuticallyacceptable solvent capable of dissolving the compound (e.g.,ethanol ormethylene chloride) to form a solution. The solvent can optionally becapable of evaporating when the solution is dried under vacuum. Anadditional carrier can be added to the solution prior to drying, such asCremophor® EL solution. The resulting solution is dried under vacuum toform a glass. The glass is then mixed with a binder to form a powder.The powder can be mixed with fillers or other conventional tablettingagents and processed to form a tablet for oral administration to apatient. The powder can also be added to any liquid carrier as describedabove to form a solution, emulsion, suspension or the like for oraladministration.

[0063] Emulsions for parenteral administration can be prepared bydissolving an antitumor compound in any pharmaceutically acceptablesolvent capable of dissolving the compound (e.g., ethanol or methylenechloride) to form a solution. An appropriate volume of a carrier whichis an emulsion, such as Liposyn® II or Liposyn® III emulsion, is addedto the solution while stirring to form a pharmaceutically acceptableemulsion for parenteral administration to a patient. If desired, suchemulsions can be formulated to contain a minimal amount of, or to befree of, ethanol or Cremophor® solution, which are known in the art tocause adverse physiological effects when administered at certainconcentrations in parenteral formulations.

[0064] Solutions for parenteral administration can be prepared bydissolving an antitumor compound in any pharmaceutically acceptablesolvent capable of dissolving the compound (e.g., ethanol or methylenechloride) to form a solution. An appropriate volume of a carrier whichis a solution, such as Cremophor® solution, is added to the solutionwhile stirring to form a pharmaceutically acceptable solution forparenteral administration to a patient. If desired, such solutions canbe formulated to contain a minimal amount of, or to be free of, ethanolor Cremophor® solution, which are known in the art to cause adversephysiological effects when administered at certain concentrations inparenteral formulations.

[0065] If desired, the emulsions or solutions described above for oralor parenteral administration can be packaged in IV bags, vials or otherconventional containers in concentrated form and diluted with anypharmaceutically acceptable liquid, such as saline, to form anacceptable taxane concentration prior to use as is known in the art.

[0066] Definitions

[0067] The terms “hydrocarbon” and “hydrocarbyl” as used herein describeorganic compounds or radicals consisting exclusively of the elementscarbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, andaryl moieties. These moieties also include alkyl, alkenyl, alkynyl, andaryl moieties substituted with other aliphatic or cyclic hydrocarbongroups, such as alkaryl, alkenaryl and alkynaryl. Unless otherwiseindicated, these moieties preferably comprise 1 to 20 carbon atoms.

[0068] The “substituted hydrocarbyl” moieties described herein arehydrocarbyl moieties which are substituted with at least one atom otherthan carbon, including moieties in which a carbon chain atom issubstituted with a hetero atom such as nitrogen, oxygen, silicon,phosphorous, boron, sulfur, or a halogen atom. These substituentsinclude halogen, heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy,hydroxy, protected hydroxy, keto, acyl, acyloxy, nitro, amino, amido,nitro, cyano, thiol, ketals, acetals, esters and ethers.

[0069] Unless otherwise indicated, the alkyl groups described herein arepreferably lower alkyl containing from one to eight carbon atoms in theprincipal chain and up to 20 carbon atoms. They may be straight orbranched chain or cyclic and include methyl, ethyl, propyl, isopropyl,butyl, hexyl and the like.

[0070] Unless otherwise indicated, the alkenyl groups described hereinare preferably lower alkenyl containing from two to eight carbon atomsin the principal chain and up to 20 carbon atoms. They may be straightor branched chain or cyclic and include ethenyl, propenyl, isopropenyl,butenyl, isobutenyl, hexenyl, and the like.

[0071] Unless otherwise indicated, the alkynyl groups described hereinare preferably lower alkynyl containing from two to eight carbon atomsin the principal chain and up to 20 carbon atoms. They may be straightor branched chain and include ethynyl, propynyl, butynyl, isobutynyl,hexynyl, and the like.

[0072] The terms “aryl” or “ar” as used herein alone or as part ofanother group denote optionally substituted homocyclic aromatic groups,preferably monocyclic or bicyclic groups containing from 6 to 12 carbonsin the ring portion, such as phenyl, biphenyl, naphthyl, substitutedphenyl, substituted biphenyl or substituted naphthyl. Phenyl andsubstituted phenyl are the more preferred aryl.

[0073] The terms “halogen” or “halo” as used herein alone or as part ofanother group refer to chlorine, bromine, fluorine, and iodine.

[0074] The terms “heterocyclo” or “heterocyclic” as used herein alone oras part of another group denote optionally substituted, fully saturatedor unsaturated, monocyclic or bicyclic, aromatic or nonaromatic groupshaving at least one heteroatom in at least one ring, and preferably 5 or6 atoms in each ring. The heterocyclo group preferably has 1 or 2 oxygenatoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring,and may be bonded to the remainder of the molecule through a carbon orheteroatom. Exemplary heterocyclo include heteroaromatics such as furyl,thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, orisoquinolinyl and the like. Exemplary substituents include one or moreof the following groups: hydrocarbyl, substituted hydrocarbyl, keto,hydroxy, protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy,aryloxy, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals,esters and ethers.

[0075] The term “heteroaromatic” as used herein alone or as part ofanother group denote optionally substituted aromatic groups having atleast one heteroatom in at least one ring, and preferably 5 or 6 atomsin each ring. The heteroaromatic group preferably has 1 or 2 oxygenatoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring,and may be bonded to the remainder of the molecule through a carbon orheteroatom. Exemplary heteroaromatics include furyl, thienyl, pyridyl,oxazolyl, pyrrolyl, indolyl, quinolinyl, or isoquinolinyl and the like.Exemplary substituents include one or more of the following groups:hydrocarbyl, substituted hydrocarbyl, keto, hydroxy, protected hydroxy,acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido,amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.

[0076] The term “acyl,” as used herein alone or as part of anothergroup, denotes the moiety formed by removal of the hydroxyl group fromthe group —COOH of an organic carboxylic acid, e.g., RC(O)—, wherein Ris R¹, R¹O—, R¹R²N—, or R¹S—, R¹ is hydrocarbyl, heterosubstitutedhydrocarbyl, or heterocyclo, and R² is hydrogen, hydrocarbyl orsubstituted hydrocarbyl.

[0077] The term “acyloxy,” as used herein alone or as part of anothergroup, denotes an acyl group as described above bonded through an oxygenlinkage (—O—), e.g., RC(O)O— wherein R is as defined in connection withthe term “acyl.”

[0078] Unless otherwise indicated, the alkoxycarbonyloxy moietiesdescribed herein comprise lower hydrocarbon or substituted hydrocarbonor substituted hydrocarbon moieties.

[0079] Unless otherwise indicated, the carbamoyloxy moieties describedherein are derivatives of carbamic acid in which one or both of theamine hydrogens is optionally replaced by a hydrocarbyl, substitutedhydrocarbyl or heterocyclo moiety.

[0080] The terms “hydroxyl protecting group” and “hydroxy protectinggroup” as used herein denote a group capable of protecting a freehydroxyl group (“protected hydroxyl”) which, subsequent to the reactionfor which protection is employed, may be removed without disturbing theremainder of the molecule. A variety of protecting groups for thehydroxyl group and the synthesis thereof may be found in “ProtectiveGroups in Organic Synthesis” by T. W. Greene, John Wiley and Sons, 1981,or Fieser & Fieser. Exemplary hydroxyl protecting groups includemethoxymethyl, 1-ethoxyethyl, benzyloxymethyl,(.beta.-trimethylsilylethoxy)methyl, tetrahydropyranyl,2,2,2-trichloroethoxycarbonyl, t-butyl(diphenyl)silyl, trialkylsilyl,trichloromethoxycarbonyl and 2,2,2-trichloroethoxymethyl.

[0081] As used herein, “Ac” means acetyl; “Bz” means benzoyl; “Et” meansethyl; “Me” means methyl; “Ph” means phenyl; “iPr” means isopropyl;“tBu” and “t-Bu” means tert-butyl; “R” means lower alkyl unlessotherwise defined; “py” means pyridine or pyridyl; “TES” meanstriethylsilyl; “TMS” means trimethylsilyl; “LAH” means lithium aluminumhydride; “10-DAB” means 10-desacetylbaccatin III”; “amine protectinggroup” includes, but is not limited to, carbamates, for example,2,2,2-trichloroethylcarbamate or tertbutylcarbamate; “protected hydroxy”means—OP wherein P is a hydroxy protecting group; “tBuOCO” and “Boc”mean tert-butoxycarbonyl; “tAmOCO” means tert-amyloxycarbonyl; “2-FuCO”means 2-furylcarbonyl; “2th” means 2-thienyl; “PhCO” meansphenylcarbonyl; “2-ThCO” means 2-thienylcarbonyl; “2-PyCO” means2-pyridylcarbonyl; “3-PyCO” means 3-pyridylcarbonyl; “4-PyCO” means4-pyridylcarbonyl; “C₄H₇CO” means butenylcarbonyl; “EtOCO” meansethoxycarbonyl; “ibueCO” means isobutenylcarbonyl; “iBuCO” meansisobutylcarbonyl; “iBuOCO” means isobutoxycarbonyl; “iPrOCO” meansisopropyloxycarbonyl; “nPrOCO” means n-propyloxycarbonyl; “nPrCO” meansn-propyl carbonyl; “ibue” means isobutenyl; “THF” means tetrahydrofuran;“DMAP” means 4-dimethylamino pyridine; “LHMDS” means LithiumHexamethylDisilazanide.

[0082] The following examples illustrate the invention.

EXAMPLE 1

[0083]

[0084] 10-Triethylsilyl-10eacetyl baccatin III. To a solution of 1.0 g(1.84 mmol) of 10-deacetyl baccatin III in 50 mL of THF at −10° C. undera nitrogen atmosphere was added 0.857 mL (2.76 mmol, 1.5 mol equiv) ofN,O-(bis)-TES-trifluoroacetamide over a period of 3 min. This wasfollowed by the addition of 0.062 mL of a 0.89 M THF solution of lithiumbis(trimethylsilyl)amide (0.055 mmol, 0.03 mol equiv). After 10 min0.038 mL (0.92 mmol, 0.5 mol equiv) of methanol was added, and after anadditional 5 min 4 mL (0.055 mmol, 0.03 mol equiv) of acetic acid wasadded. The solution was diluted with 300 mL of ethyl acetate and washedtwo times with 100 mL of saturated aqueous sodium bicarbonate solution.The combined aqueous layers were extracted with 100 mL of ethyl acetateand the combined organic layers were washed with brine, dried oversodium sulfate, and concentrated under reduced pressure. To the residuewas added 100 mL of hexane and the solid (1.23 g, 101%) was collected byfiltration. Recrystallization of the solid by dissolving in boilingethyl acetate (20 mL, 17 mL/g) and cooling to room temperature gave1.132 g (94%) of a white solid. m.p. 242° C.; [α]_(D) ²⁵−60.4 (c 0.7,CHCl₃); ¹H NMR (CDCl₃, 400 MHz) δ (p.p.m): 8.10 (2H, d, Jm=7.5 Hz, Bzo),7.60 (1H, t, Jm=7.5 Hz, Bzp), 7.47 (2H, t, Jo=7.5 Hz, Bzm), 5.64 (1H, d,J3=6.9 Hz, H2), 5.26 (1H, s, H10), 4.97 (1H, dd, J6β=2.2 Hz, J6α=9.9 Hz,H5), 4.85 (1H, dd, J14α=8.9 Hz, J14β=8.9 Hz, H13), 4.30 (1H, d, J20β=8.5Hz, H20α), 4.23 (1H, ddd, J7OH=4.5 Hz, J6α=6.6 Hz, J6β=11.0 Hz, H7),4.15 (1H, d, J20α=8.5 Hz, H20β), 4.00 (1H, d, J2=6.9 Hz, H3), 2.58 (1H,ddd, J7=6.6 Hz, J5=9.9 Hz, J6β=14.5 Hz, H6α), 2.28-2.25 (5H, m, 4Ac,H14α, H14β), 2.02 (3H, s, 18Me), 1.97 (1H, d, J7=4.5 Hz, H7OH), 1.78(1H, ddd, J7=11.0 Hz, J5=2.2 Hz, J6α=14.5 Hz, H6β), 1.68 (3H, s, 19Me),1.56 (1H, s, OH1), 1.32 (1H, d, J13=8.8 Hz, OH13), 1.18 (3H, s, 17Me),1.06 (3H, s, 16 Me), 0.98 (9H, t, JCH₂(TES)=7.3 Hz, CH₃(TES)), 0.65 (6H,dq, JCH₃(TES)=7.3 Hz, CH₂(TES)).

[0085] 10-Triethylsilyl-10-deacetyl-7-methoxycarbonyl baccatin III. To asolution of 9.3 g (14.1 mmol) of 10-triethylsilyl-10-deacetyl baccatinIII and 10.35 g (84.6 mmol) of DMAP in 500 mL of dichloromethane at 0°C. under a nitrogen atmosphere was added 2.15 mL (22.7 mmol, 1.5 molequiv) of methyl chloroformate. The mixture was stirred at 0° C. for 4h, diluted with 300 mL of saturated aqueous ammonium chloride solutionand extracted twice with 200 mL of ethyl acetate. The organic layer waswashed with 500 mL of 10% aqueous copper sulfate solution, 500 mL ofsaturated aqueous sodium bicarbonate solution, 100 mL of brine, driedover sodium sulfate and concentrated under reduced pressure. The crudeproduct was recrystallized from ethyl acetate to give 8.92 g (88%) of10-triethylsilyl-10-deacetyl-7-methoxycarbonyl baccatin III. m.p.260-262° C.; [α]_(D) ²⁵ −54.3 (c 0.89, CHCl₃); ¹H NMR (CDCl₃, 500 MHz) δ(ppm): 8.10 (2H, d, Jm=8.5 Hz, Bzo), 7.60 (1H, t, Jm=8.5 Hz, Bzp), 7.47(2H, t, Jo=8.5 Hz, Bzm), 5.64 (1H, d, J3=7.0 Hz, H2), 5.31 (1H, dd,J6α=7.0 Hz, J6β=10.0 Hz, H7), 5.28 (1H, s, H10), 4.96 (1H, d, J6α=8.5Hz, H5), 4.86 (1H, t, J14α=14.0 Hz, J14β=7.0 Hz, H13), 4.31 (1H, d,J20β=8.0 Hz, H20α), 4.16 (1H, d, J20α=8.0Hz, H20β), 4.06 (1H, d, J2=7.0Hz, H3), 3.77 (3H, s, OMe) 2.65 (1H, ddd, J7=7.0 Hz, J5=8.5 Hz, J6β=10.0Hz, H6α), 2.29-2.26 (5H, m, 4Ac, H14α, H14β), 2.08 (3H, s, 18Me), 2.01(1H, d, 13OH), 1.92 (3H, ddd, J7=10.0 Hz, J5=2.3 Hz, J6α=10.0 Hz, H6β),1.80 (3H, s, 19Me), 1.18 (3H, s, 17Me), 1.05 (3H, s, 16Me), 0.97 (9H, t,JCH₂(TES)=8.0 Hz, CH₃(TES)), 0.59 (6H, dq, JCH₃(TES)=8.0 Hz, CH₂(TES)).

[0086]2′-O-MOP-3′-desphenyl-3′-(2-thienyl)-10-triethylsilyl-7-methoxycarbonyltaxotere. To a solution of 495 mg (0.690 mmol) of10-triethylsilyl-10-deacetyl-7-methoxycarbonyl baccatin III in 4 mL ofanhydrous THF under a nitrogen atmosphere at −45° C. was added 0.72 mL(0.72 mmol) of a 1M solution of LiHMDS in THF. After 0.5 h a solution of278 mg (0.814 mmol) of the b-Lactam in 2 mL of anhydrous THF was added.The mixture was warmed to 0° C., and after 2 h 0.5 mL of saturatedaqueous sodium bicarbonate solution was added. The mixture was dilutedwith 50 ml of ethyl acetate and washed two times with 5 mL of brine. Theorganic phase was dried over sodium sulfate and concentrated underreduced pressure to give a slightly yellow solid. The solid wasrecrystallized by dissolving it in 12 mL of a 1:5 mixture of ethylacetate and hexane at reflux and then cooling to room temperature togive 679 mg (93%) of a white crystalline solid which was used directlyin the next reaction.

[0087] 3′-Desphenyl-3′-(2-thienyl)-7-methoxycarbonyl taxotere. To asolution of 211 mg (0.199 mmol) of2′-O-MOP-3′-desphenyl-3′-(2-thienyl)-10-triethylsilyl-7-methoxycarbonyltaxotere in 1.7 mL of pyridine and 5.4 mL of acetonitrile at 0° C. wasadded 0.80 mL (2.0 mmol) of an aqueous solution containing 49% HF. Themixture was warmed to room temperature for 14 h and was then dilutedwith 20 mL of ethyl acetate and washed three times with 2 mL ofsaturated aqueous sodium bicarbonate and then with 8 mL of brine. Theorganic phase was dried over sodium sulfate and concentrated underreduced pressure to give 174 mg (100%) of a white solid. The crudeproduct was crystallized with 2 mL of solvent (CH₂Cl₂:hexane=1:1.7) togive 168 mg (97%) of white crystals. m.p. 142.5-143° C.; [a]_(D) ²⁵−25.1 (c 0.53, CHCl₃); Anal. Calcd for C₄₃H₅₃NO₁₆S: C, 59.23; H, 6.13.Found: C, 58.99; H, 6.25. ¹H NMR (500 MHz, CDCl₃): Proton d (ppm)Pattern J (Hz)  2 5.69 d H3(6.5) o-benzoate 8.12 d m-benzoate(7.5)m-benzoate 7.51 t o-benzoate(7.5), p-benzoate(7.5) p-benzoate 7.62 tm-benzoate(7.5)  3 4.01 d H2(6.5) 4Ac 2.39 s  5 4.93 d H6a(8.0) 6a 2.53ddd H7(7.5), H5(9.5), H6b(15.0) 6b 2.00 ddd H7(11.0), H5(2.5), H6a(15.0) 7 5.29 dd H6a(7.5), H6b(11.0) OMe 3.76 s 10 5.39 s 10-OH 4.06 br s 136.23 t H14a(9.0), H14b(9.0) 14a + 14b 2.34 m 16Me 1.11 s 17Me 1.23 s18Me 1.93 s 19Me 1.86 s 20a 4.33 d H20b(8.5) 20b 4.21 d H20a(8.5)  2′4.64 br 2′OH 3.43 br  3′ 5.51 br  3″ 7.10 d H4″(3.5)  4″ 7.01 ddH5″(5.0), H3″(3.5)  5″ 7.28 d H4″(5.0) NH 5.34 d H3′(9.5) (CH3)3C 1.35 s

EXAMPLE 2

[0088] The procedures described in Example 1 were repeated, but othersuitably protected β-lactams were substituted for the β-lactam ofExample 1 to prepare the series of compounds having structural formula(13) and the combinations of substituents identified in the followingtable. (13)

Compound X₅ X₃ R₇ 4144 iPrOCO— 2-thienyl MeOCOO— 4151 iPrOCO— 2-thienylEtOCOO— 4164 ibueCO— 2-thienyl EtOCOO— 4188 PhCO— 2-thienyl EtOCOO— 42222-FuCO— 2-thienyl MeOCOO— 4234 tBuOCO— 2-thienyl EtOCOO— 4244 ibueCO—2-thienyl MeOCOO— 4262 tBuOCO— 2-thienyl MeOCOO— 4304 2-FuCO— 2-thienylEtOCOO— 4355 iBuOCO— 2-thienyl MeOCOO— 4363 iBuOCO— 2-thienyl EtOCOO—4411 PhCO— 2-thienyl MeOCOO— 4424 2-ThCO 2-thienyl MeOCOO— 4434 tBuOCO—3-furyl MeOCOO— 4455 2-ThCO 2-thienyl EtOCOO— 4474 tBuOCO— 3-thienylMeOCOO— 4484 tBuOCO— isobutenyl MeOCOO— 4500 tBuOCO— 3-thienyl EtOCOO—4515 iBuOCO— 3-thienyl AcO— 4524 tBuOCO— isobutenyl EtOCOO— 4533 tBuOCO—2-furyl MeOCOO— 4555 tBuOCO— cyclopropyl AcO— 4584 iBuOCO— 3-furylMeOCOO— 4566 tBuOCO— cyclopropyl MeOCOO— 4575 tBuOCO— 2-furyl MeOCOO—4624 iBuOCO— 3-furyl EtOCOO— 4644 iBuOCO— isobutenyl MeOCOO— 4656iBuOCO— 2-furyl MeOCOO— 4674 iBuOCO— 3-thienyl MeOCOO— 4688 iBuOCO—isobutenyl EtOCOO— 4696 iBuOCO— 2-furyl EtOCOO— 4744 tC₃H₅CO— 2-furylMeOCOO— 4766 tC₃H₅CO— 2-thienyl MeOCOO— 5466 ibueCO— 2-furyl BnOCOO—6151 ibueCO— 2-furyl EtOCOO— 6246 tAmOCO— 2-furyl BnOCOO— 5433 tBuOCO—2-furyl BnOCOO— 4818 tC₃H₅CO— 2-furyl EtOCOO— 6566 tC₃H₅CO— 2-thienylBnOCOO— 4855 tC₃H₅CO— 2-thienyl EtOCOO— 4464 tBuOCO— 3-furyl EtOCOO—4904 tC₃H₅CO— 3-furyl EtOCOO— 4877 tC₃H₅CO— 3-furyl MeOCOO— 4979 iBuOCO—3-thienyl EtOCOO— 4444 tBuOCO— 3-thienyl MeOCOO— 4999 tC₃H₅CO— 3-thienylEtOCOO— 4969 tC₃H₅CO— 3-thienyl MeOCOO— 5225 iBuOCO— cpro EtOCOO— 5211iBuOCO— cpro MeOCOO— 5165 tBuOCO— cpro EtOCOO—

EXAMPLE 3

[0089] Following the processes described in Example 1 and elsewhereherein, the following specific taxanes having structural formula 14 maybe prepared, wherein R₇ is as previously defined, including wherein R₇is R_(7a)OCOO— and R_(7a) is (i) substituted or unsubstituted C₁ to C₈alkyl (straight, branched or cyclic), such as methyl, ethyl, propyl,butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C₂ to C₈alkenyl (straight, branched or cyclic), such as ethenyl, propenyl,butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C₂ toC₈ alkynyl (straight or branched) such as ethynyl, propynyl, butynyl,pentynyl, or hexynyl; (iv) substituted or unsubstituted phenyl; or (v)substituted or unsubstituted heterocyclo such as furyl, thienyl, orpyridyl. The substituents may be hydrocarbyl or any of the heteroatomcontaining substituents selected from the group consisting ofheterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protectedhydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal, acetal, esterand ether moieties, but not phosphorous containing moieties. (14)

X₅ X₃ R₇ tBuOCO— 2-furyl R_(a)OCOO— tBuOCO— 3-furyl R_(a)OCOO— tBuOCO—2-thienyl R_(a)OCOO— tBuOCO— 3-thienyl R_(a)OCOO— tBuOCO— 2-pyridylR_(a)OCOO— tBuOCO— 3-pyridyl R_(a)OCOO— tBuOCO— 4-pyridyl R_(a)OCOO—tBuOCO— isobutenyl R_(a)OCOO— tBuOCO— isopropyl R_(a)OCOO— tBuOCO—cyclopropyl R_(a)OCOO— tBuOCO— cyclobutyl R_(a)OCOO— tBuOCO— cyclopentylR_(a)OCOO— tBuOCO— phenyl R_(a)OCOO— benzoyl 2-furyl R_(a)OCOO— benzoyl3-furyl R_(a)OCOO— benzoyl 2-thienyl R_(a)OCOO— benzoyl 3-thienylR_(a)OCOO— benzoyl 2-pyridyl R_(a)OCOO— benzoyl 3-pyridyl R_(a)OCOO—benzoyl 4-pyridyl R_(a)OCOO— benzoyl isobutenyl R_(a)OCOO— benzoylisopropyl R_(a)OCOO— benzoyl cyclopropyl R_(a)OCOO— benzoyl cyclobutylR_(a)OCOO— benzoyl cyclopentyl R_(a)OCOO— benzoyl phenyl R_(a)OCOO—2-FuCO— 2-furyl R_(a)OCOO— 2-FuCO— 3-furyl R_(a)OCOO— 2-FuCO— 2-thienylR_(a)OCOO— 2-FuCO— 3-thienyl R_(a)OCOO— 2-FuCO— 2-pyridyl R_(a)OCOO—2-FuCO— 3-pyridyl R_(a)OCOO— 2-FuCO— 4-pyridyl R_(a)OCOO— 2-FuCO—isobutenyl R_(a)OCOO— 2-FuCO— isopropyl R_(a)OCOO— 2-FuCO— cyclopropylR_(a)OCOO— 2-FuCO— cyclobutyl R_(a)OCOO— 2-FuCO— cyclopentyl R_(a)OCOO—2-FuCO— phenyl R_(a)OCOO— 2-ThCO— 2-furyl R_(a)OCOO— 2-ThCO— 3-furylR_(a)OCOO— 2-ThCO— 2-thienyl R_(a)OCOO— 2-ThCO— 3-thienyl R_(a)OCOO—2-ThCO— 2-pyridyl R_(a)OCOO— 2-ThCO— 3-pyridyl R_(a)OCOO— 2-ThCO—4-pyridyl R_(a)OCOO— 2-ThCO— isobutenyl R_(a)OCOO— 2-ThCO— isopropylR_(a)OCOO— 2-ThCO— cyclopropyl R_(a)OCOO— 2-ThCO— cyclobutyl R_(a)OCOO—s2-ThCO— cyclopentyl R_(a)OCOO— 2-ThCO— phenyl R_(a)OCOO— 2-PyCO—2-furyl R_(a)OCOO— 2-PyCO— 3-furyl R_(a)OCOO— 2-PyCO— 2-thienylR_(a)OCOO— 2-PyCO— 3-thienyl R_(a)OCOO— 2-PyCO— 2-pyridyl R_(a)OCOO—2-PyCO— 3-pyridyl R_(a)OCOO— 2-PyCO— 4-pyridyl R_(a)OCOO— 2-PyCO—isobutenyl R_(a)OCOO— 2-PyCO— isopropyl R_(a)OCOO— 2-PyCO— cyclopropylR_(a)OCOO— 2-PyCO— cyclobutyl R_(a)OCOO— 2-PyCO— cyclopentyl R_(a)OCOO—2-PyCO— phenyl R_(a)OCOO— 3-PyCO— 2-furyl R_(a)OCOO— 3-PyCO— 3-furylR_(a)OCOO— 3-PyCO— 2-thienyl R_(a)OCOO— 3-PyCO— 3-thienyl R_(a)OCOO—3-PyCO— 2-pyridyl R_(a)OCOO— 3-PyCO— 3-pyridyl R_(a)OCOO— 3-PyCO—4-pyridyl R_(a)OCOO— 3-PyCO— isobutenyl R_(a)OCOO— 3-PyCO— isopropylR_(a)OCOO— 3-PyCO— cyclopropyl R_(a)OCOO— 3-PyCO— cyclobutyl R_(a)OCOO—3-PyCO— cyclopentyl R_(a)OCOO— 3-PyCO— phenyl R_(a)OCOO— 4-PyCO— 2-furylR_(a)OCOO— 4-PyCO— 3-furyl R_(a)OCOO— 4-PyCO— 2-thienyl R_(a)OCOO—4-PyCO— 3-thienyl R_(a)OCOO— 4-PyCO— 2-pyridyl R_(a)OCOO— 4-PyCO—3-pyridyl R_(a)OCOO— 4-PyCO— 4-pyridyl R_(a)OCOO— 4-PyCO— isobutenylR_(a)OCOO— 4-PyCO— isopropyl R_(a)OCOO— 4-PyCO- cyclopropyl R_(a)OCOO—4-PyCO- cyclobutyl R_(a)OCOO— 4-PyCO- cyclopentyl R_(a)OCOO— 4-PyCO-phenyl R_(a)OCOO— C₄H₇CO— 2-furyl R_(a)OCOO— C₄H₇CO— 3-furyl R_(a)OCOO—C₄H₇CO— 2-thienyl R_(a)OCOO— C₄H₇CO— 3-thienyl R_(a)OCOO— C₄H₇CO—2-pyridyl R_(a)OCOO— C₄H₇CO— 3-pyridyl R_(a)OCOO— C₄H₇CO— 4-pyridylR_(a)OCOO— C₄H₇CO— isobutenyl R_(a)OCOO— C₄H₇CO— isopropyl R_(a)OCOO—C₄H₇CO— cyclopropyl R_(a)OCOO— C₄H₇CO— cyclobutyl R_(a)OCOO— C₄H₇CO—cyclopentyl R_(a)OCOO— C₄H₇CO— phenyl R_(a)OCOO— EtOCO— 2-furylR_(a)OCOO— EtOCO— 3-furyl R_(a)OCOO— EtOCO— 2-thienyl R_(a)OCOO— EtOCO—3-thienyl R_(a)OCOO— EtOCO— 2-pyridyl R_(a)OCOO— EtOCO— 3-pyridylR_(a)OCOO— EtOCO— 4-pyridyl R_(a)OCOO— EtOCO— isobutenyl R_(a)OCOO—EtOCO— isopropyl R_(a)OCOO— EtOCO— cyclopropyl R_(a)OCOO— EtOCO—cyclobutyl R_(a)OCOO— EtOCO— cyclopentyl R_(a)OCOO— EtOCO— phenylR_(a)OCOO— ibueCO— 2-furyl R_(a)OCOO— ibueCO— 3-furyl R_(a)OCOO— ibueCO—2-thienyl R_(a)OCOO— ibueCO— 3-thienyl R_(a)OCOO— ibueCO— 2-pyridylR_(a)OCOO— ibueCO— 3-pyridyl R_(a)OCOO— ibueCO— 4-pyridyl R_(a)OCOO—ibueCO— isobutenyl R_(a)OCOO— ibueCO— isopropyl R_(a)OCOO— ibueCO—cyclopropyl R_(a)OCOO— ibueCO— cyclobutyl R_(a)OCOO— ibueCO— cyclopentylR_(a)OCOO— ibueCO— phenyl R_(a)OCOO— iBuCO— 2-furyl R_(a)OCOO— iBuCO—3-furyl R_(a)OCOO— iBuCO— 2-thienyl R_(a)OCOO— iBuCO— 3-thienylR_(a)OCOO— iBuCO— 2-pyridyl R_(a)OCOO— iBuCO— 3-pyridyl R_(a)OCOO—iBuCO— 4-pyridyl R_(a)OCOO— iBuCO— isobutenyl R_(a)OCOO— IBuCO—isopropyl R_(a)OCOO— iBuCO— cyclopropyl R_(a)OCOO— iBuCO— cyclobutylR_(a)OCOO— iBuCO— cyclopentyl R_(a)OCOO— iBuCO— phenyl R_(a)OCOO—iBuOCO— 2-furyl R_(a)OCOO— iBuOCO— 3-furyl R_(a)OCOO— iBuOCO— 2-thienylR_(a)OCOO— iBuOCO— 3-thienyl R_(a)OCOO— iBuOCO— 2-pyridyl R_(a)OCOO—iBuOCO— 3-pyridyl R_(a)OCOO— iBuOCO— 4-pyridyl R_(a)OCOO— iBuOCO—isobutenyl R_(a)OCOO— iBuOCO— isopropyl R_(a)OCOO— iBuOCO— cyclopropylR_(a)OCOO— iBuOCO— cyclobutyl R_(a)OCOO— iBuOCO— cyclopentyl R_(a)OCOO—iBuOCO— phenyl R_(a)OCOO— iPrOCO— 2-furyl R_(a)OCOO— iPrOCO— 3-furylR_(a)OCOO— iPrOCO— 2-thienyl R_(a)OCOO— iPrOCO— 3-thienyl R_(a)OCOO—iPrOCO— 2-pyridyl R_(a)OCOO— iPrOCO— 3-pyridyl R_(a)OCOO— iPrOCO—4-pyridyl R_(a)OCOO— iPrOCO— isobutenyl R_(a)OCOO— iPrOCO— isopropylR_(a)OCOO— iPrOCO— cyclopropyl R_(a)OCOO— iPrOCO— cyclobutyl R_(a)OCOO—iPrOCO— cyclopentyl R_(a)OCOO— iPrOCO— phenyl R_(a)OCOO— nPrOCO— 2-furylR_(a)OCOO— nPrOCO— 3-furyl R_(a)OCOO— nPrOCO— 2-thienyl R_(a)OCOO—nPrOCO— 3-thienyl R_(a)OCOO— nPrOCO— 2-pyridyl R_(a)OCOO— nPrOCO—3-pyridyl R_(a)OCOO— nPrOCO— 4-pyridyl R_(a)OCOO— nPrOCO— isobutenylR_(a)OCOO— nPrOCO— isopropyl R_(a)OCOO— nPrOCO— cyclopropyl R_(a)OCOO—nPrOCO— cyclobutyl R_(a)OCOO— nPrOCO— cyclopentyl R_(a)OCOO— nPrOCO—phenyl R_(a)OCOO— nPrCO— 2-furyl R_(a)OCOO— nPrCO— 3-furyl R_(a)OCOO—nPrCO— 2-thienyl R_(a)OCOO— nPrCO— 3-thienyl R_(a)OCOO— nPrCO— 2-pyridylR_(a)OCOO— nPrCO— 3-pyridyl R_(a)OCOO— nPrCO— 4-pyridyl R_(a)OCOO—nPrCO— isobutenyl R_(a)OCOO— nPrCO— isopropyl R_(a)OCOO— nPrCO—cyclopropyl R_(a)OCOO— nPrCO— cyclobutyl R_(a)OCOO— nPrCO— cyclopentylR_(a)OCOO— nPrCO— phenyl R_(a)OCOO— tBuOCO— 2-furyl EtOCOO— tBuOCO—2-pyridyl EtOCOO— tBuOCO— 3-pyridyl EtOCOO— tBuOCO— 4-pyridyl EtOCOO—tBuOCO— isopropyl EtOCOO— tBuOCO— cyclopropyl EtOCOO— tBuOCO— cyclobutylEtOCOO— tBuOCO— cyclopentyl EtOCOO— tBuOCO— phenyl EtOCOO— benzoyl2-furyl EtOCOO— benzoyl 3-furyl EtOCOO— benzoyl 3-thienyl EtOCOO—benzoyl 2-pyridyl EtOCOO— benzoyl 3-pyridyl EtOCOO— benzoyl 4-pyridylEtOCOO— benzoyl isobutenyl EtOCOO— benzoyl isopropyl EtOCOO— benzoylcyclopropyl EtOCOO— benzoyl cyclobutyl EtOCOO— benzoyl cyclopentylEtOCOO— benzoyl phenyl EtOCOO— 2-FuCO— 2-furyl EtOCOO— 2-FuCO— 3-furylEtOCOO— 2-FuCO— 3-thienyl EtOCOO— 2-FuCO— 2-pyridyl EtOCOO— 2-FuCO—3-pyridyl EtOCOO— 2-FuCO— 4-pyridyl EtOCOO— 2-FuCO— isobutenyl EtOCOO—2-FuCO— isopropyl EtOCOO— 2-FuCO— cyclopropyl EtOCOO— 2-FuCO— cyclobutylEtOCOO— 2-FuCO— cyclopentyl EtOCOO— 2-FuCO— phenyl EtOCOO— 2-ThCO—2-furyl EtOCOO— 2-ThCO— 3-furyl EtOCOO— 2-ThCO— 3-thienyl EtOCOO—2-ThCO— 2-pyridyl EtOCOO— 2-ThCO— 3-pyridyl EtOCOO— 2-ThCO— 4-pyridylEtOCOO— 2-ThCO— isobutenyl EtOCOO— 2-ThCO— isopropyl EtOCOO— 2-ThCO—cyclopropyl EtOCOO— 2-ThCO— cyclobutyl EtOCOO— 2-ThCO— cyclopentylEtOCOO— 2-ThCO— phenyl EtOCOO— 2-PyCO— 2-furyl EtOCOO— 2-PyCO— 3-furylEtOCOO— 2-PyCO— 2-thienyl EtOCOO— 2-PyCO— 3-thienyl EtOCOO— 2-PyCO—2-pyridyl EtOCOO— 2-PyCO— 3-pyridyl EtOCOO— 2-PyCO— 4-pyridyl EtOCOO—2-PyCO— isobutenyl EtOCOO— 2-PyCO— isopropyl EtOCOO— 2-PyCO— cyclopropylEtOCOO— 2-PyCO— cyclobutyl EtOCOO— 2-PyCO— cyclopentyl EtOCOO— 2-PyCO—phenyl EtOCOO— 3-PyCO— 2-furyl EtOCOO— 3-PyCO— 3-furyl EtOCOO— 3-PyCO—2-thienyl EtOCOO— 3-PyCO— 3-thienyl EtOCOO— 3-PyCO— 2-pyridyl EtOCOO—3-PyCO— 3-pyridyl EtOCOO— 3-PyCO— 4-pyridyl EtOCOO— 3-PyCO— isobutenylEtOCOO— 3-PyCO— isopropyl EtOCOO— 3-PyCO— cyclopropyl EtOCOO— 3-PyCO—cyclobutyl EtOCOO— 3-PyCO— cyclopentyl EtOCOO— 3-PyCO— phenyl EtOCOO—4-PyCO— 2-furyl EtOCOO— 4-PyCO— 3-furyl EtOCOO— 4-PyCO— 2-thienylEtOCOO— 4-PyCO— 3-thienyl EtOCOO— 4-PyCO— 2-pyridyl EtOCOO— 4-PyCO—3-pyridyl EtOCOO— 4-PyCO— 4-pyridyl EtOCOO— 4-PyCO— isobutenyl EtOCOO—4-PyCO— isopropyl EtOCOO— 4-PyCO— cyclopropyl EtOCOO— 4-PyCO— cyclobutylEtOCOO— 4-PyCO— cyclopentyl EtOCOO— 4-PyCO— phenyl EtOCOO— C₄H₇CO—2-furyl EtOCOO— C₄H₇CO— 3-furyl EtOCOO— C₄H₇CO— 2-thienyl EtOCOO—C₄H₇CO— 3-thienyl EtOCOO— C₄H₇CO— 2-pyridyl EtOCOO— C₄H₇CO— 3-pyridylEtOCOO— C₄H₇CO— 4-pyridyl EtOCOO— C₄H₇CO— isobutenyl EtOCOO— C₄H₇CO—isopropyl EtOCOO— C₄H₇CO— cyclopropyl EtOCOO— C₄H₇CO— cyclobutyl EtOCOO—C₄H₇CO— cyclopentyl EtOCOO— C₄H₇CO— phenyl EtOCOO— EtOCO— 2-furylEtOCOO— EtOCO— 3-furyl EtOCOO— EtOCO— 2-thienyl EtOCOO— EtOCO— 3-thienylEtOCOO— EtOCO— 2-pyridyl EtOCOO— EtOCO— 3-pyridyl EtOCOO— EtOCO—4-pyridyl EtOCOO— EtOCO— isobutenyl EtOCOO— EtOCO— isopropyl EtOCOO—EtOCO— cyclopropyl EtOCOO— EtOCO— cyclobutyl EtOCOO— EtOCO— cyclopentylEtOCOO— EtOCO— phenyl EtOCOO— ibueCO— 3-furyl EtOCOO— ibueCO— 3-thienylEtOCOO— ibueCO— 2-pyridyl EtOCOO— ibueCO— 3-pyridyl EtOCOO— ibueCO—4-pyridyl EtOCOO— ibueCO— isobutenyl EtOCOO— ibueCO— isopropyl EtOCOO—ibueCO— cyclopropyl EtOCOO— ibueCO— cyclobutyl EtOCOO— ibueCO—cyclopentyl EtOCOO— ibueCO— phenyl EtOCOO— iBuCO— 2-furyl EtOCOO— iBuCO—3-furyl EtOCOO— iBuCO— 2-thienyl EtOCOO— iBuCO— 3-thienyl EtOCOO— iBuCO—2-pyridyl EtOCOO— iBuCO— 3-pyridyl EtOCOO— iBuCO— 4-pyridyl EtOCOO—iBuCO— isobutenyl EtOCOO— iBuCO— isopropyl EtOCOO— iBuCO— cyclopropylEtOCOO— iBuCO— cyclobutyl EtOCOO— iBuCO— cyclopentyl EtOCOO— iBuCO—phenyl EtOCOO— iBuOCO— 3-furyl EtOCOO— iBuOCO— 2-pyridyl EtOCOO— iBuOCO—3-pyridyl EtOCOO— iBuOCO— 4-pyridyl EtOCOO— iBuOCO— isopropyl EtOCOO—iBuOCO— cyclopropyl EtOCOO— iBuOCO— cyclobutyl EtOCOO— iBuOCO—cyclopentyl EtOCOO— iBuOCO— phenyl EtOCOO— iPrOCO— 2-furyl EtOCOO—iPrOCO— 3-furyl EtOCOO— iPrOCO— 3-thienyl EtOCOO— iPrOCO— 2-pyridylEtOCOO— iPrOCO— 3-pyridyl EtOCOO— iPrOCO— 4-pyridyl EtOCOO— iPrOCO—isobutenyl EtOCOO— iPrOCO— isopropyl EtOCOO— iPrOCO— cyclopropyl EtOCOO—iPrOCO— cyclobutyl EtOCOO— iPrOCO— cyclopentyl EtOCOO— iPrOCO— phenylEtOCOO— nPrOCO— 2-furyl EtOCOO— nPrOCO— 3-furyl EtOCOO— nPrOCO—2-thienyl EtOCOO— nPrOCO— 3-thienyl EtOCOO— nPrOCO— 2-pyridyl EtOCOO—nPrOCO— 3-pyridyl EtOCOO— nPrOCO— 4-pyridyl EtOCOO— nPrOCO— isobutenylEtOCOO— nPrOCO— isopropyl EtOCOO— nPrOCO— cyclopropyl EtOCOO— nPrOCO—cyclobutyl EtOCOO— nPrOCO— cyclopentyl EtOCOO— nPrOCO— phenyl EtOCOO—nPrCO— 2-furyl EtOCOO— nPrCO— 3-furyl EtOCOO— nPrCO— 2-thienyl EtOCOO—nPrCO— 3-thienyl EtOCOO— nPrCO— 2-pyridyl EtOCOO— nPrCO— 3-pyridylEtOCOO— nPrCO— 4-pyridyl EtOCOO— nPrCO— isobutenyl EtOCOO— nPrCO—isopropyl EtOCOO— nPrCO— cyclopropyl EtOCOO— nPrCO— cyclobutyl EtOCOO—nPrCO— cyclopentyl EtOCOO— nPrCO— phenyl EtOCOO— tBuOCO— 2-pyridylMeOCOO— tBuOCO— 3-pyridyl MeOCOO— tBuOCO— 4-pyridyl MeOCOO— tBuOCO—isopropyl MeOCOO— tBuOCO— cyclobutyl MeOCOO— tBuOCO— cyclopentyl MeOCOO—tBuOCO— phenyl MeOCOO— benzoyl 2-furyl MeOCOO— benzoyl 3-furyl MeOCOO—benzoyl 3-thienyl MeOCOO— benzoyl 2-pyridyl MeOCOO— benzoyl 3-pyridylMeOCOO— benzoyl 4-pyridyl MeOCOO— benzoyl isobutenyl MeOCOO— benzoylisopropyl MeOCOO— benzoyl cyclopropyl MeOCOO— benzoyl cyclobutyl MeOCOO—benzoyl cyclopentyl MeOCOO— benzoyl phenyl MeOCOO— 2-FuCO— 2-furylMeOCOO— 2-FuCO— 3-furyl MeOCOO— 2-FuCO— 3-thienyl MeOCOO— 2-FuCO—2-pyridyl MeOCOO— 2-FuCO— 3-pyridyl MeOCOO— 2-FuCO— 4-pyridyl MeOCOO—2-FuCO— isobutenyl MeOCOO— 2-FuCO— isopropyl MeOCOO— 2-FuCO— cyclopropylMeOCOO— 2-FuCO— cyclobutyl MeOCOO— 2-FuCO— cyclopentyl MeOCOO— 2-FuCO—phenyl MeOCOO— 2-ThCO— 2-furyl MeOCOO— 2-ThCO— 3-furyl MeOCOO— 2-ThCO—3-thienyl MeOCOO— 2-ThCO— 2-pyridyl MeOCOO— 2-ThCO— 3-pyridyl MeOCOO—2-ThCO— 4-pyridyl MeOCOO— 2-ThCO— isobutenyl MeOCOO— 2-ThCO— isopropylMeOCOO— 2-ThCO— cyclopropyl MeOCOO— 2-ThCO— cyclobutyl MeOCOO— 2-ThCO—cyclopentyl MeOCOO— 2-ThCO— phenyl MeOCOO— 2-PyCO— 2-furyl MeOCOO—2-PyCO— 3-furyl MeOCOO— 2-PyCO— 2-thienyl MeOCOO— 2-PyCO— 3-thienylMeOCOO— 2-PyCO— 2-pyridyl MeOCOO— 2-PyCO— 3-pyridyl MeOCOO— 2-PyCO—4-pyridyl MeOCOO— 2-PyCO— isobutenyl MeOCOO— 2-PyCO— isopropyl MeOCOO—2-PyCO— cyclopropyl MeOCOO— 2-PyCO— cyclobutyl MeOCOO— 2-PyCO—cyclopentyl MeOCOO— 2-PyCO— phenyl MeOCOO— 3-PyCO— 2-furyl MeOCOO—3-PyCO— 3-furyl MeOCOO— 3-PyCO— 2-thienyl MeOCOO— 3-PyCO— 3-thienylMeOCOO— 3-PyCO— 2-pyridyl MeOCOO— 3-PyCO— 3-pyridyl MeOCOO— 3-PyCO—4-pyridyl MeOCOO— 3-PyCO— isobutenyl MeOCOO— 3-PyCO— isopropyl MeOCOO—3-PyCO— cyclopropyl MeOCOO— 3-PyCO— cyclobutyl MeOCOO— 3-PyCO—cyclopentyl MeOCOO— 3-PyCO— phenyl MeOCOO— 4-PyCO— 2-furyl MeOCOO—4-PyCO— 3-furyl MeOCOO— 4-PyCO— 2-thienyl MeOCOO— 4-PyCO— 3-thienylMeOCOO— 4-PyCO— 2-pyridyl MeOCOO— 4-PyCO— 3-pyridyl MeOCOO— 4-PyCO—4-pyridyl MeOCOO— 4-PyCO— isobutenyl MeOCOO— 4-PyCO— isopropyl MeOCOO—4-PyCO— cyclopropyl MeOCOO— 4-PyCO— cyclobutyl MeOCOO— 4-PyCO—cyclopentyl MeOCOO— 4-PyCO— phenyl MeOCOO— C₄H₇CO— 2-furyl MeOCOO₄H₇CO—C₄H₇CO— 3-furyl MeOCOO₄H₇CO— C₄H₇CO— 2-thienyl MeOCOO₄H₇CO— C₄H₇CO—3-thienyl MeOCOO₄H₇CO— C₄H₇CO— 2-pyridyl MeOCOO₄H₇CO— C₄H₇CO— 3-pyridylMeOCOO₄H₇CO— C₄H₇CO— 4-pyridyl MeOCOO₄H₇CO— C₄H₇CO— isobutenylMeOCOO₄H₇CO— C₄H₇CO— isopropyl MeOCOO₄H₇CO— C₄H₇CO— cyclopropylMeOCOO₄H₇CO— C₄H₇CO— cyclobutyl MeOCOO₄H₇CO— C₄H₇CO— cyclopentylMeOCOO₄H₇CO— C₄H₇CO— phenyl MeOCOO₄H₇CO— EtOCO— 2-furyl MeOCOO— EtOCO—3-furyl MeOCOO— EtOCO— 2-thienyl MeOCOO— EtOCO— 3-thienyl MeOCOO— EtOCO—2-pyridyl MeOCOO— EtOCO— 3-pyridyl MeOCOO— EtOCO— 4-pyridyl MeOCOO—EtOCO— isobutenyl MeOCOO— EtOCO— isopropyl MeOCOO— EtOCO— cyclopropylMeOCOO— EtOCO— cyclobutyl MeOCOO— EtOCO— cyclopentyl MeOCOO— EtOCO—phenyl MeOCOO— ibueCO— 2-furyl MeOCOO— ibueCO— 3-furyl MeOCOO— ibueCO—3-thienyl MeOCOO— ibueCO— 2-pyridyl MeOCOO— ibueCO— 3-pyridyl MeOCOO—ibueCO— 4-pyridyl MeOCOO— ibueCO— isobutenyl MeOCOO— ibueCO— isopropylMeOCOO— ibueCO— cyclopropyl MeOCOO— ibueCO— cyclobutyl MeOCOO— ibueCO—cyclopentyl MeOCOO— ibueCO— phenyl MeOCOO— iBuCO— 2-furyl MeOCOO— iBuCO—3-furyl MeOCOO— iBuCO— 2-thienyl MeOCOO— iBuCO— 3-thienyl MeOCOO— iBuCO—2-pyridyl MeOCOO— iBuCO— 3-pyridyl MeOCOO— IBuCO— 4-pyridyl MeOCOO—iBuCO— isobutenyl MeOCOO— iBuCO— isopropyl MeOCOO— iBuCO— cyclopropylMeOCOO— iBuCO— cyclobutyl MeOCOO— iBuCO— cyclopentyl MeOCOO— iBuCO—phenyl MeOCOO— iBuOCO— 2-pyridyl MeOCOO— iBuOCO— 3-pyridyl MeOCOO—iBuOCO— 4-pyridyl MeOCOO— iBuOCO— isopropyl MeOCOO— iBuOCO— cyclopropylMeOCOO— iBuOCO— cyclobutyl MeOCOO— iBuOCO— cyclopentyl MeOCOO— iBuOCO—phenyl MeOCOO— iPrOCO— 2-furyl MeOCOO— iPrOCO— 3-furyl MeOCOO— iPrOCO—3-thienyl MeOCOO— iPrOCO— 2-pyridyl MeOCOO— iPrOCO— 3-pyridyl MeOCOO—iPrOCO— 4-pyridyl MeOCOO— iPrOCO— isobutenyl MeOCOO— iPrOCO— isopropylMeOCOO— iPrOCO— cyclopropyl MeOCOO— iPrOCO— cyclobutyl MeOCOO— iPrOCO—cyclopentyl MeOCOO— iPrOCO— phenyl MeOCOO— nPrOCO— 2-furyl MeOCOO—nPrOCO— 3-furyl MeOCOO— nPrOCO— 2-thienyl MeOCOO— nPrOCO— 3-thienylMeOCOO— nPrOCO— 2-pyridyl MeOCOO— nPrOCO— 3-pyridyl MeOCOO— nPrOCO—4-pyridyl MeOCOO— nPrOCO— isobutenyl MeOCOO— nPrOCO— isopropyl MeOCOO—nPrOCO— cyclopropyl MeOCOO— nPrOCO— cyclobutyl MeOCOO— nPrOCO—cyclopentyl MeOCOO— nPrOCO— phenyl MeOCOO— nPrCO— 2-furyl MeOCOO— nPrCO—3-furyl MeOCOO— nPrCO— 2-thienyl MeOCOO— nPrCO— 3-thienyl MeOCOO— nPrCO—2-pyridyl MeOCOO— nPrCO— 3-pyridyl MeOCOO— nPrCO— 4-pyridyl MeOCOO—nPrCO— isobutenyl MeOCOO— nPrCO— isopropyl MeOCOO— nPrCO— cyclopropylMeOCOO— nPrCO— cyclobutyl MeOCOO— nPrCO— cyclopentyl MeOCOO— nPrCO—phenyl MeOCOO—

EXAMPLE 4

[0090] Following the processes described in Example 1 and elsewhereherein, the following specific taxanes having structural formula 15 maybe prepared, wherein in each of the series (that is, each of series “A”through “K”) R₁₀ is hydroxy and R₇ is as previously defined, includingwherein R₇ is R_(7a)OCOO— and R_(7a) is (i) substituted orunsubstituted, preferably unsubstituted, C₂ to C₈ alkyl (straight,branched or cyclic), such as ethyl, propyl, butyl, pentyl, or hexyl;(ii) substituted or unsubstituted, preferably unsubstituted, C₂ to C₈alkenyl (straight, branched or cyclic), such as ethenyl, propenyl,butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted,preferably unsubstituted, C₂ to C₈ alkynyl (straight or branched) suchas ethynyl, propynyl, butynyl, pentynyl, or hexynyl; (iv) substituted orunsubstituted, preferably unsubstituted, phenyl; or (v) substituted orunsubstituted, preferably unsubstituted, heteroaromatic such as furyl,thienyl, or pyridyl.

[0091] In the “A” series of compounds, X₁₀ is as otherwise as definedherein. Preferably, heterocyclo is substituted or unsubstitued furyl,thienyl, or pyridyl, X₁₀ is substituted or unsubstitued furyl, thienyl,pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), and R₇ and R₁₀ eachhave the beta stereochemical configuration.

[0092] In the “B” series of compounds, X₁₀ and R_(2a) are as otherwiseas defined herein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), R_(2a) is preferably substituted or unsubstitued furyl,thienyl, pyridyl, phenyl, or lower alkyl, and R₇ and R₁₀ each have thebeta stereochemical configuration.

[0093] In the “C” series of compounds, X₁₀ and R_(9a) are as otherwiseas defined herein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), R_(9a) is preferably substituted or unsubstitued furyl,thienyl, pyridyl, phenyl, or lower alkyl, and R₇, R₉ and R₁₀ each havethe beta stereochemical configuration.

[0094] In the “D” and “E” series of compounds, X₁₀ is as otherwise asdefined herein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), and R₇, R₉ (series D only) and R₁₀ each have the betastereochemical configuration.

[0095] In the “F” series of compounds, X₁₀, R_(2a) and R_(9a) are asotherwise as defined herein. Preferably, heterocyclo is preferablysubstituted or unsubstitued furyl, thienyl, or pyridyl, X₁₀ ispreferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl,or lower alkyl (e.g., tert-butyl), R_(2a) is preferably substituted orunsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R₇, R₉and R₁₀ each have the beta stereochemical configuration.

[0096] In the “G” series of compounds, X₁₀ and R_(2a) are as otherwiseas defined herein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), R_(2a) is preferably substituted or unsubstitued furyl,thienyl, pyridyl, phenyl, or lower alkyl, and R₇, R₉ and R₁₀ each havethe beta stereochemical configuration.

[0097] In the “H” series of compounds, X₁₀ is as otherwise as definedherein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), R_(2a) is preferably substituted or unsubstitued furyl,thienyl, pyridyl, phenyl, or lower alkyl, and R₇ and R₁₀ each have thebeta stereochemical configuration.

[0098] In the “I” series of compounds, X₁₀ and R_(2a) are as otherwiseas defined herein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), R_(2a) is preferably substituted or unsubstitued furyl,thienyl, pyridyl, phenyl, or lower alkyl, and R₇ and R₁₀ each have thebeta stereochemical configuration.

[0099] In the “J” series of compounds, X₁₀ and R_(2a) are as otherwiseas defined herein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), R_(2a) is preferably substituted or unsubstitued furyl,thienyl, pyridyl, phenyl, or lower alkyl, and R₇, R₉ and R₁₀ each havethe beta stereochemical configuration.

[0100] In the “K” series of compounds, X₁₀, R_(2a) and R_(9a) are asotherwise as defined herein. Preferably, heterocyclo is preferablysubstituted or unsubstitued furyl, thienyl, or pyridyl, X₁₀ ispreferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl,or lower alkyl (e.g., tert-butyl), R_(2a) is preferably substituted orunsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R₇, R₉and R₁₀ each have the beta stereochemical configuration.

[0101] Any substituents of each X₃, X₅, R₂, R₇, and R₉ may behydrocarbyl or any of the heteroatom containing substituents selectedfrom the group consisting of heterocyclo, alkoxy, alkenoxy, alkynoxy,aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido,thiol, ketal, acetal, ester and ether moieties, but not phosphorouscontaining moieties. (15)

Series X₅ X₃ R₇ R₂ R₉ R₁₄ A1 —COOX₁₀ heterocyclo R_(7a)OCOO— C₆H₅COO— OH A2 —COX₁₀ heterocyclo R_(7a)OCOO— C₆H₅COO— O H A3 —CONHX₁₀ heterocycloR_(7a)OCOO— C₆H₅COO— O H A4 —COOX₁₀ optionally R_(7a)OCOO— C₆H₅COO— O Hsubstituted C₂ to C₈ alkyl A5 —COX₁₀ optionally R_(7a)OCOO— C₆H₅COO— O Hsubstituted C₂ to C₈ alkyl A6 —CONHX₁₀ optionally R_(7a)OCOO— C₆H₅COO— OH substituted C₂ to C₈ alkyl A7 —COOX₁₀ optionally R_(7a)OCOO— C₆H₅COO—O H substituted C₂ to C₈ alkenyl A8 —COX₁₀ optionally R_(7a)OCOO—C₆H₅COO— O H substituted C₂ to C₈ alkenyl A9 —CONHX₁₀ optionallyR_(7a)OCOO— C₆H₅COO— O H substituted C₂ to C₈ alkenyl A10 —COOX₁₀optionally R_(7a)OCOO— C₆H₅COO— O H substituted C₂ to C₈ alkynyl A11—COX₁₀ optionally R_(7a)OCOO— C₆H₅COO— O H substituted C₂ to C₈ alkynylA12 —CONHX₁₀ optionally R_(7a)OCOO— C₆H₅COO— O H substituted C₂ to C₈alkynyl B1 —COOX₁₀ heterocyclo R_(7a)OCOO— R_(2a)COO— O H B2 —COX₁₀heterocyclo R_(7a)OCOO— R_(2a)COO— O H B3 —CONHX₁₀ heterocycloR_(7a)OCOO— R_(2a)COO— O H B4 —COOX₁₀ optionally R_(7a)OCOO— R_(2a)COO—O H substituted C₂ to C₈ alkyl B5 —COX₁₀ optionally R_(7a)OCOO—R_(2a)COO— O H substituted C₂ to C₈ alkyl B6 —CONHX₁₀ optionallyR_(7a)OCOO— R_(2a)COO— O H substituted C₂ to C₈ alkyl B7 —COOX₁₀optionally R_(7a)OCOO— R_(2a)COO— O H substituted C₂ to C₈ alkenyl B8—COX₁₀ optionally R_(7a)OCOO— R_(2a)COO— O H substituted C₂ to C₈alkenyl B9 —CONHX₁₀ optionally R_(7a)OCOO— R_(2a)COO— O H substituted C₂to C₈ alkenyl B10 —COOX₁₀ optionally R_(7a)OCOO— R_(2a)COO— O Hsubstituted C₂ to C₈ alkynyl B11 —COX₁₀ optionally R_(7a)OCOO—R_(2a)COO— O H substituted C₂ to C₈ alkynyl B12 —CONHX₁₀ optionallyR_(7a)OCOO— R_(2a)COO— O H substituted C₂ to C₈ alkynyl C1 —COOX₁₀heterocyclo R_(7a)OCOO— C₆H₅COO— R_(9a)COO— H C2 —COX₁₀ heterocycloR_(7a)OCOO— C₆H₅COO— R_(9a)COO— H C3 —CONHX₁₀ heterocyclo R_(7a)OCOO—C₆H₅COO— R_(9a)COO— H C4 —COOX₁₀ optionally R_(7a)OCOO— C₆H₅COO—R_(9a)COO— H substituted C₂ to C₈ alkyl C5 —COX₁₀ optionally R_(7a)OCOO—C₆H₅COO— R_(9a)COO— H substituted C₂ to C₈ alkyl C6 —CONHX₁₀ optionallyR_(7a)OCOO— C₆H₅COO— R_(9a)COO— H substituted C₂ to C₈ alkyl C7 —COOX₁₀optionally R_(7a)OCOO— C₆H₅COO— R_(9a)COO— H substituted C₂ to C₈alkenyl C8 —COX₁₀ optionally R_(7a)OCOO— C₆H₅COO— R_(9a)COO— Hsubstituted C₂ to C₈ alkenyl C9 —CONHX₁₀ optionally R_(7a)OCOO— C₆H₅COO—R_(9a)COO— H substituted C₂ to C₈ alkenyl C10 —COOX₁₀ optionallyR_(7a)OCOO— C₆H₅COO— R_(9a)COO— H substituted C₂ to C₈ alkynyl C11—COX₁₀ optionally R_(7a)OCOO— C₆H₅COO— R_(9a)COO— H substituted C₂ to C₈alkynyl C12 —CONHX₁₀ optionally R_(7a)OCOO— C₆H₅COO— R_(9a)COO— Hsubstituted C₂ to C₈ alkynyl D1 —COOX₁₀ heterocyclo R_(7a)OCOO— C₆H₅COO—OH H D2 —COX₁₀ heterocyclo R_(7a)OCOO— C₆H₅COO— OH H D3 —CONHX₁₀heterocyclo R_(7a)OCOO— C₆H₅COO— OH H D4 —COOX₁₀ optionally R_(7a)OCOO—C₆H₅COO— OH H substituted C₂ to C₈ alkyl D5 —COX₁₀ optionallyR_(7a)OCOO— C₆H₅COO— OH H substituted C₂ to C₈ alkyl D6 —CONHX₁₀optionally R_(7a)OCOO— C₆H₅COO— OH H substituted C₂ to C₈ alkyl D7—COOX₁₀ optionally R_(7a)OCOO— C₆H₅COO— OH H substituted C₂ to C₈alkenyl D8 —COX₁₀ optionally R_(7a)OCOO— C₆H₅COO— OH H substituted C₂ toC₈ alkenyl D9 —CONHX₁₀ optionally R_(7a)OCOO— C₆H₅COO— OH H substitutedC₂ to C₈ alkenyl D10 —COOX₁₀ optionally R_(7a)OCOO— C₆H₅COO— OH Hsubstituted C₂ to C₈ alkynyl D11 —COX₁₀ optionally R_(7a)OCOO— C₆H₅COO—OH H substituted C₂ to C₈ alkynyl D12 —CONHX₁₀ optionally R_(7a)OCOO—C₆H₅COO— OH H substituted C₂ to C₈ alkynyl E1 —COOX₁₀ heterocycloR_(7a)OCOO— C₆H₅COO— O OH E2 —COX₁₀ heterocyclo R_(7a)OCOO— C₆H₅COO— OOH E3 —CONHX₁₀ heterocyclo R_(7a)OCOO— C₆H₅COO— O OH E4 —COOX₁₀optionally R_(7a)OCOO— C₆H₅COO— O OH substituted C₂ to C₈ alkyl E5—COX₁₀ optionally R_(7a)OCOO— C₆H₅COO— O OH substituted C₂ to C₈ alkylE6 —CONHX₁₀ optionally R_(7a)OCOO— C₆H₅COO— O OH substituted C₂ to C₈alkyl E7 —COOX₁₀ optionally R_(7a)OCOO— C₆H₅COO— O OH substituted C₂ toC₈ alkenyl E8 —COX₁₀ optionally R_(7a)OCOO— C₆H₅COO— O OH substituted C₂to C₈ alkenyl E9 —CONHX₁₀ optionally R_(7a)OCOO— C₆H₅COO— O OHsubstituted C₂ to C₈ alkenyl E10 —COOX₁₀ optionally R_(7a)OCOO— C₆H₅COO—O OH substituted C₂ to C₈ alkynyl E11 —COX₁₀ optionally R_(7a)OCOO—C₆H₅COO— O OH substituted C₂ to C₈ alkynyl E12 —CONHX₁₀ optionallyR_(7a)OCOO— C₆H₅COO— O OH substituted C₂ to C₈ alkynyl F1 —COOX₁₀heterocyclo R_(7a)OCOO— R_(2a)COO— R_(9a)COO— H F2 —COX₁₀ heterocycloR_(7a)OCOO— R_(2a)COO— R_(9a)COO— H F3 —CONHX₁₀ heterocyclo R_(7a)OCOO—R_(2a)COO— R_(9a)COO— H F4 —COOX₁₀ optionally R_(7a)OCOO— R_(2a)COO—R_(9a)COO— H substituted C₂ to C₈ alkyl F5 —COX₁₀ optionally R_(7a)OCOO—R_(2a)COO— R_(9a)COO— H substituted C₂ to C₈ alkyl F6 —CONHX₁₀optionally R_(7a)OCOO— R_(2a)COO— R_(9a)COO— H substituted C₂ to C₈alkyl F7 —COOX₁₀ optionally R_(7a)OCOO— R_(2a)COO— R_(9a)COO— Hsubstituted C₂ to C₈ alkenyl F8 —COX₁₀ optionally R_(7a)OCOO— R_(2a)COO—R_(9a)COO— H substituted C₂ to C₈ alkenyl F9 —CONHX₁₀ optionallyR_(7a)OCOO— R_(2a)COO— R_(9a)COO— H substituted C₂ to C₈ alkenyl F10—COOX₁₀ optionally R_(7a)OCOO— R_(2a)COO— R_(9a)COO— H substituted C₂ toC₈ alkynyl F11 —COX₁₀ optionally R_(7a)OCOO— R_(2a)COO— R_(9a)COO— Hsubstituted C₂ to C₈ alkynyl F12 —CONHX₁₀ optionally R_(7a)OCOO—R_(2a)COO— R_(9a)COO— H substituted C₂ to C₈ alkynyl G1 —COOX₁₀heterocyclo R_(7a)OCOO— R_(2a)COO— OH H G2 —COX₁₀ heterocycloR_(7a)OCOO— R_(2a)COO— OH H G3 —CONHX₁₀ heterocyclo R_(7a)OCOO—R_(2a)COO— OH H G4 —COOX₁₀ optionally R_(7a)OCOO— R_(2a)COO— OH Hsubstituted C₂ to C₈ alkyl G5 —COX₁₀ optionally R_(7a)OCOO— R_(2a)COO—OH H substituted C₂ to C₈ alkyl G6 —CONHX₁₀ optionally R_(7a)OCOO—R_(2a)COO— OH H substituted C₂ to C₈ alkyl G7 —COOX₁₀ optionallyR_(7a)OCOO— R_(2a)COO— OH H substituted C₂ to C₈ alkenyl G8 —COX₁₀optionally R_(7a)OCOO— R_(2a)COO— OH H substituted C₂ to C₈ alkenyl G9—CONHX₁₀ optionally R_(7a)OCOO— R_(2a)COO— OH H substituted C₂ to C₈alkenyl G10 —COOX₁₀ optionally R_(7a)OCOO— R_(2a)COO— OH H substitutedC₂ to C₈ alkynyl G11 —COX₁₀ optionally R_(7a)OCOO— R_(2a)COO— OH Hsubstituted C₂ to C₈ alkynyl G12 —CONHX₁₀ optionally R_(7a)OCOO—R_(2a)COO— OH H substituted C₂ to C₈ alkynyl H1 —COOX₁₀ heterocycloR_(7a)OCOO— C₆H₅COO— OH OH H2 —COX₁₀ heterocyclo R_(7a)OCOO— C₆H₅COO— OHOH H3 —CONHX₁₀ heterocyclo R_(7a)OCOO— C₆H₅COO— OH OH H4 —COOX₁₀optionally R_(7a)OCOO— C₆H₅COO— OH OH substituted C₂ to C₈ alkyl H5—COX₁₀ optionally R_(7a)OCOO— C₆H₅COO— OH OH substituted C₂ to C₈ alkylH6 —CONHX₁₀ optionally R_(7a)OCOO— C₆H₅COO— OH OH substituted C₂ to C₈alkyl H7 —COOX₁₀ optionally R_(7a)OCOO— C₆H₅COO— OH OH substituted C₂ toC₈ alkenyl H8 —COX₁₀ optionally R_(7a)OCOO— C₆H₅COO— OH OH substitutedC₂ to C₈ alkenyl H9 —CONHX₁₀ optionally R_(7a)OCOO— C₆H₅COO— OH OHsubstituted C₂ to C₈ alkenyl H10 —COOX₁₀ optionally R_(7a)OCOO— C₆H₅COO—OH OH substituted C₂ to C₈ alkynyl H11 —COX₁₀ optionally R_(7a)OCOO—C₆H₅COO— OH OH substituted C₂ to C₈ alkynyl H12 —CONHX₁₀ optionallyR_(7a)OCOO— C₆H₅COO— OH OH substituted C₂ to C₈ alkynyl I1 —COOX₁₀heterocyclo R_(7a)OCOO— R_(2a)COO— O OH I2 —COX₁₀ heterocycloR_(7a)OCOO— R_(2a)COO— O OH I3 —CONHX₁₀ heterocyclo R_(7a)OCOO—R_(2a)COO— O OH I4 —COOX₁₀ optionally R_(7a)OCOO— R_(2a)COO— O OHsubstituted C₂ to C₈ alkyl I5 —COX₁₀ optionally R_(7a)OCOO— R_(2a)COO— OOH substituted C₂ to C₈ alkyl I6 —CONHX₁₀ optionally R_(7a)OCOO—R_(2a)COO— O OH substituted C₂ to C₈ alkyl I7 —COOX₁₀ optionallyR_(7a)OCOO— R_(2a)COO— O OH substituted C₂ to C₈ alkenyl I8 —COX₁₀optionally R_(7a)OCOO— R_(2a)COO— O OH substituted C₂ to C₈ alkenyl I9—CONHX₁₀ optionally R_(7a)OCOO— R_(2a)COO— O OH substituted C₂ to C₈alkenyl I10 —COOX₁₀ optionally R_(7a)OCOO— R_(2a)COO— O OH substitutedC₂ to C₈ alkynyl I11 —COX₁₀ optionally R_(7a)OCOO— R_(2a)COO— O OHsubstituted C₂ to C₈ alkynyl I12 —CONHX₁₀ optionally R_(7a)OCOO—R_(2a)COO— O OH substituted C₂ to C₈ alkynyl J1 —COOX₁₀ heterocycloR_(7a)OCOO— R_(2a)COO— OH OH J2 —COX₁₀ heterocyclo R_(7a)OCOO—R_(2a)COO— OH OH J3 —CONHX₁₀ heterocyclo R_(7a)OCOO— R_(2a)COO— OH OH J4—COOX₁₀ optionally R_(7a)OCOO— R_(2a)COO— OH OH substituted C₂ to C₈alkyl J5 —COX₁₀ optionally R_(7a)OCOO— R_(2a)COO— OH OH substituted C₂to C₈ alkyl J6 —CONHX₁₀ optionally R_(7a)OCOO— R_(2a)COO— OH OHsubstituted C₂ to C₈ alkyl J7 —COOX₁₀ optionally R_(7a)OCOO— R_(2a)COO—OH OH substituted C₂ to C₈ alkenyl J8 —COX₁₀ optionally R_(7a)OCOO—R_(2a)COO— OH OH substituted C₂ to C₈ alkenyl J9 —CONHX₁₀ optionallyR_(7a)OCOO— R_(2a)COO— OH OH substituted C₂ to C₈ alkenyl J10 —COOX₁₀optionally R_(7a)OCOO— R_(2a)COO— OH OH substituted C₂ to C₈ alkynyl J11—COX₁₀ optionally R_(7a)OCOO— R_(2a)COO— OH OH substituted C₂ to C₈alkynyl J12 —CONHX₁₀ optionally R_(7a)OCOO— R_(2a)COO— OH OH substitutedC₂ to C₈ alkynyl K1 —COOX₁₀ heterocyclo R_(7a)OCOO— R_(2a)COO—R_(9a)COO— OH K2 —COX₁₀ heterocyclo R_(7a)OCOO— R_(2a)COO— R_(9a)COO— OHK3 —CONHX₁₀ heterocyclo R_(7a)OCOO— R_(2a)COO— R_(9a)COO— OH K4 —COOX₁₀optionally R_(7a)OCOO— R_(2a)COO— R_(9a)COO— OH substituted C₂ to C₈alkyl K5 —COX₁₀ optionally R_(7a)OCOO— R_(2a)COO— R_(9a)COO— OHsubstituted C₂ to C₈ alkyl K6 —CONHX₁₀ optionally R_(7a)OCOO— R_(2a)COO—R_(9a)COO— OH substituted C₂ to C₈ alkyl K7 —COOX₁₀ optionallyR_(7a)OCOO— R_(2a)COO— R_(9a)COO— OH substituted C₂ to C₈ alkenyl K8—COX₁₀ optionally R_(7a)OCOO— R_(2a)COO— R_(9a)COO— OH substituted C₂ toC₈ alkenyl K9 —CONHX₁₀ optionally R_(7a)OCOO— R_(2a)COO— R_(9a)COO— OHsubstituted C₂ to C₈ alkenyl K10 —COOX₁₀ optionally R_(7a)OCOO—R_(2a)COO— R_(9a)COO— OH substituted C₂ to C₈ alkynyl K11 —COX₁₀optionally R_(7a)OCOO— R_(2a)COO— R_(9a)COO— OH substituted C₂ to C₈alkynyl K12 —CONHX₁₀ optionally R_(7a)OCOO— R_(2a)COO— R_(9a)COO— OHsubstituted C₂ to C₈ alkynyl

EXAMPLE 5 In Vitro Cytotoxicity Measured by the Cell Colony FormationAssay

[0102] Four hundred cells (HCT116) were plated in 60 mm Petri dishescontaining 2.7 mL of medium (modified McCoy's 5a medium containing 10%fetal bovine serum and 100 units/mL penicillin and 100 g/mLstreptomycin). The cells were incubated in a CO₂ incubator at 37° C. for5 h for attachment to the bottom of Petri dishes. The compoundsidentified in Example 2 were made up fresh in medium at ten times thefinal concentration, and then 0.3 mL of this stock solution was added tothe 2.7 mL of medium in the dish. The cells were then incubated withdrugs for 72 h at 37° C. At the end of incubation the drug-containingmedia were decanted, the dishes were rinsed with 4 mL of Hank's BalanceSalt Solution (HBSS), 5 mL of fresh medium was added, and the disheswere returned to the incubator for colony formation. The cell colonieswere counted using a colony counter after incubation for 7 days. Cellsurvival was calculated and the values of ID50 (the drug concentrationproducing 50% inhibition of colony formation) were determined for eachtested compound. IN VITRO Compound ID 50 (nm) HCT116 taxol 2.1 docetaxel0.6 4144 <1 4151 <1 4164 <1 4188 <10 4222 <1 4234 <1 4244 <1 4262 <14304 <10 4355 <1 4363 <10 4411 <1 4424 <1 4434 <1 4455 <1 4474 <1 4484<1 4500 <1 4515 <10 4524 <1 4533 <1 4555 <1 4584 <10 4566 <1 4575 <14624 <10 4644 <10 4656 <1 4674 <1 4688 <10 4696 <1 4744 <1 4766 <1 5466<1 6151 <1 6246 <1 5433 <1 4818 <1 6566 <10 4855 <1 4464 <1 4904 <104877 <1 4979 <10 4444 <1 4999 <1 4969 <1 5225 <10 5211 <10 5165 <1

1. A method of inhibiting tumor growth in a mammal, said method comprising administering a therapeutically effective amount of a composition comprising at least one pharmaceutically acceptable carrier and a taxane having the formula

wherein X₃ is 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, isobutenyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl; X₅ is —COX₁₀ and X₁₀ is isobutenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, butenyl, isobutyl or n-propyl or X₅ is —COOX₁₀ and X₁₀ is ethyl, n-propyl, isopropyl, or isobutyl; R₂ is benzoyloxy; R₇ is R_(7a)OCOO—; R₁₀ is hydroxy; and R_(7a) is methyl or ethyl:
 2. The method of claim 1 wherein X₃ is 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, isobutenyl or cyclopropyl and X₅ is —COX₁₀ and X₁₀ is isobutenyl, 2-furyl or 2-thienyl or X₅ is —COOX₁₀ and X₁₀ is isopropyl or isobutyl.
 3. The method of claim 1 wherein X₃ is thienyl.
 4. The method of claim 1 wherein X₃ is 2-thienyl.
 5. The method of claim 1 wherein X₃ is furyl.
 6. The method of claim 1 wherein X₃ is 2-furyl.
 7. The method of claim 1 wherein R_(7a) is methyl.
 8. The method of claim 1 wherein R_(7a) is ethyl.
 9. The method of claim 1 wherein X₅ is —COOX₁₀ and X₁₀ is isopropyl.
 10. The method of claim 7 wherein X₃ is thienyl.
 11. The method of claim 7 wherein X₃ is 2-thienyl.
 12. The method of claim 7 wherein X₃ is furyl.
 13. The method of claim 7 wherein X₃ is 2-furyl.
 14. The method of claim 8 wherein X₃ is thienyl.
 15. The method of claim 8 wherein X₃ is 2-thienyl.
 16. The method of claim 8 wherein X₃ is furyl.
 17. The method of claim 8 wherein X₃ is 2-furyl.
 18. The method of claim 9 wherein X₃ is thienyl.
 19. The method of claim 9 wherein X₃ is 2-thienyl.
 20. The method of claim 9 wherein X₃ is furyl.
 21. The method of claim 9 wherein X₃ is 2-furyl.
 22. A method of inhibiting tumor growth in a mammal, said method comprising administering a therapeutically effective amount of a composition comprising at least one pharmaceutically acceptable carrier and a taxane having the formula

wherein X₃ is 2-furyl, 3-furyl, 2-thienyl or 3-thienyl; X₅ is —COX₁₀ and X₁₀ is trans-propenyl; R₂ is benzoyloxy; R₇ is R_(7a)OCOO—; R₁₀ is hydroxy; and R_(7a) is methyl or ethyl.
 23. The method of claim 22 wherein R_(7a) is methyl.
 24. The method of claim 22 wherein R_(7a) is ethyl.
 25. The method of claim 23 wherein X₃ is thienyl.
 26. The method of claim 23 wherein X₃ is 2-thienyl.
 27. The method of claim 23 wherein X₃ is furyl.
 28. The method of claim 23 wherein X₃ is 2-furyl.
 29. The method of claim 24 wherein X₃ is thienyl.
 30. The method of claim 24 wherein X₃ is 2-thienyl.
 31. The method of claim 24 wherein X₃ is furyl.
 32. The method of claim 24 wherein X₃ is 2-furyl.
 33. A method of inhibiting tumor growth in a mammal, said method comprising administering a therapeutically effective amount of a composition comprising at least one pharmaceutically acceptable carrier and a taxane having the formula

wherein X₃ is 2-furyl; X₅ is —COX₁₀ and X₁₀ is isobutenyl or X₅ is —COOX₁₀ and X₁₀ is t-butyl or t-amyl; R₂ is benzoyloxy; R₇ is R_(7a)OCOO—; R₁₀ is hydroxy; and R_(7a) is benzyl.
 34. A method for preparing a pharmaceutical composition comprising mixing at least one nonaqueous, pharmaceutically acceptable solvent and a taxane having the formula

wherein R₂ is acyloxy; R₇ is carbonate; R₉ is keto, hydroxy, or acyloxy; R₁₀ is hydroxy; R₁₄ is hydrido or hydroxy; X₃ is substituted or unsubstituted alkyl, alkenyl, alkynyl or heterocyclo; X₅ is —COX₁₀, —COOX₁₀, or —CONHX₁₀; X₁₀ is hydrocarbyl, substituted hydrocarbyl, or heterocyclo; and Ac is acetyl.
 37. The method of claim 36 wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 38. The method of claim 36 wherein R₇ is R_(7a)OCOO— and R_(7a) is methyl or ethyl.
 39. The method of claim 36 wherein X₅ is —COX₁₀ and X₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl, or X₅ is —COOX₁₀ and X₁₀ is substituted or unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 40. The method of claim 36 wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl, R₇ is R_(7a)OCOO— and R_(7a) is methyl or ethyl.
 41. The method of claim 36 wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl, X₅ is —COX₁₀ and X₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl, or X₅ is —COOX₁₀ and X₁₀ is substituted or unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 42. The method of claim 36 wherein R₇ is R_(7a)OCOO— and R_(7a) is methyl or ethyl, X₅ is —COX₁₀ and X₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl, or X₅ is —COOX₁₀ and X₁₀ is substituted or unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 43. The method of claim 36 wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl, R₇ is R_(7a)OCOO—, R_(7a) is methyl or ethyl, X₅ is —COX₁₀ and X₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl, or X₅ is —COOX₁₀ and X₁₀ is substituted or unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 44. The method of claim 36 wherein X₃ is thienyl.
 45. The method of claim 36 wherein X₃ is 2-thienyl.
 46. The method of claim 36 wherein X₃ is furyl.
 47. The method of claim 36 wherein X₃ is 2-furyl. 